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The expression of DBC1/CCAR2 is associated with poor prognosis of ovarian carcinoma

The expression of DBC1/CCAR2 is associated with poor prognosis of ovarian carcinoma Background: Recent reports have shown that deleted in breast cancer 1 (DBC1/CCAR2) is an indicator of poor prognosis of various human cancers. However, its expression in ovarian carcinoma has not been reported. Methods: We investigated the immunohistochemical expression of DBC1 and BRCA1 and their prognostic significance in 104 ovarian carcinomas. Survival analyses were performed according to the Kaplan-Meier method, as well as univariate and multivariate Cox proportional hazard regression analysis. Results: Positive expression of DBC1 and BRCA1 were seen in 63% (66/104) and 44% (46/104) of overall ovarian carcinomas, respectively. DBC1 expression was significantly associated with advanced clinicopathological factors such as high tumor stage, latent distant metastasis, platinum-resistance, elevated serum levels of CA125, high histologic grade, and BRCA1 expression. In the histological subtypes of ovarian carcinomas, DBC1 expression was more common in serous carcinoma (72%, 54/75) than mucinous carcinoma (15%, 3/20). BRCA1 expression was significantly associated with latent distant metastasis, platinum-resistance, and higher histologic grade. In addition, DBC1 expression was significantly associated with shorter overall survival (OS) and relapse-free survival (RFS) in 104 ovarian carcinomas (OS; P < 0.001, RFS; P < 0.001) and 63 high-grade serous carcinomas (OS; P = 0.008, RFS; P = 0.023) by univariate analysis. BRCA1 expression was significantly associated with OS and RFS in 104 ovarian carcinomas (OS; P = 0.005, RFS; P =0.002) and 75 serous carcinomas (OS; P = 0.047, RFS; P = 0.038) by univariate analysis. Moreover, DBC1 expression was an independent prognostic indicator for OS in both 104 ovarian carcinomas (P= 0.021) and 63 high-grade serous carcinomas (P= 0.011) by multivariate analysis. Conclusions: These results indicate that the expression of DBC1 and BRCA1 are closely related with in the progression of ovarian carcinomas and may have clinical utility in the prediction of prognosis of ovarian carcinomas. Especially, DBC1 expression could be employed as a significant prognostic indicator for ovarian carcinomas especially in high-grade serous carcinomas. Keywords: Ovarian neoplasms, Serous carcinoma, Deleted in breast cancer 1, BRCA1, Prognosis Background suppressor [1]. Based on data of cBio Cancer Genomics Deleted in breast cancer 1/cell cycle and apoptosis regu- Portal (http://www.cbioportal.org), the deletion of DBC1 lator 2 (DBC1/CCAR2) was named by its deletion at a has been reported in 2.5% (8/316) to 7.7% (24/311) of region 8p22 in breast cancer. Thereafter, DBC1 was re- ovarian serous carcinomas [2,3]. Especially, the inhibitory designated CCAR2 to eliminate possible confusion with role of DBC1 on SIRT1 supported the possibility that deleted in bladder cancer 1 and because it has partial se- DBC1 could be tumor suppressor because SIRT1 inacti- quence homology to CCAR1. The deletion of DBC1 in vates various tumor suppressors, especially p53 [4,5]. How- breast cancer suggested it may have a role as a tumor ever, these findings were followed by conflicting reports, which cast doubt on whether DBC1 is tumor suppressor. * Correspondence: kyjang@chonbuk.ac.kr In human cancers, the deletion of DBC1 was not a com- Departments of Pathology, Chonbuk National University Medical School, mon phenomenon and the balance between SIRT1 and Research Institute of Clinical Medicine and Research Institute for Endocrine DBC1 was disrupted in human cancers [6]. When the Sciences, Jeonju, Republic of Korea Full list of author information is available at the end of the article © 2015 Cho et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cho et al. Journal of Ovarian Research (2015) 8:2 Page 2 of 11 interaction between SIRT1 and DBC1 is week, the de- and 20 patients showed platinum-resistance. Platinum- pletion of DBC1 makes cells susceptible to UV-induced resistance was evaluated according to the standard genotoxic stress [7]. Also, DBC1 inhibits senescence of Gynecologic Oncology Group criteria [25]. The patients premalignant cells by disrupting the SUV39H1-SIRT1 who experienced recurrence or progression of ovarian complex [8]. Moreover, the expression of both DBC1 and cancer within the six months of platinum-based chemo- SIRT1 were correlated with advanced clinicopathological therapy were included in platinum-resistant group. Among characteristics and poor prognosis of human malignant tu- the 104 ovarian carcinoma patients, 39 patients experi- mors [9-16]. In addition, it has been shown that DBC1 has enced relapse and 50 patients died from ovarian carcinoma multiple functions involved in the regulation of cell survival, at the endpoint of follow-up. The five- and ten-year overall energy metabolism, and intracellular signal transduction survival (OS) rates were 57% and 50%, respectively. This [8,12,17-21]. Therefore, DBC1 might have its own role in study was approved by the institutional review board of tumorigenesis in addition to an inhibitory role for SIRT1. Chonbuk National University Hospital. Informed consent The tumorigenic role of DBC1, although controversial, was provided according to the Declaration of Helsinki. is supported by its role in the inhibition of tumor sup- All histologic slides and clinicopathologic factors were pressors [8,22] and activation of nuclear receptors with reviewed according to the criteria of the World Health tumorigenic potential [21]. DBC1 inhibits the tumor Organization classification of tumors of female repro- suppressor BRCA1 by binding to the BRCT domain in ductive organs [26]. The ovarian carcinomas included in breast cancer [22]. Defect of BRCA1/2 is involved in the this study, according to the histologic types, were 75 ser- development of ovarian carcinomas and defects in ous carcinomas (12 low-grade serous carcinomas and 63 BRCA1/2 are associated with the resistance to platinum- high-grade serous carcinomas), 20 mucinous carcinomas, based chemotherapy in ovarian carcinomas [23,24]. There- 5 endometrioid carcinomas, 3 clear cell carcinomas, and fore, there is a possibility that DBC1 may be involved in one malignant Brenner tumor. Tumor stage was reviewed BRCA1/2-related progression of ovarian carcinomas. In according to the guidelines of the tumor, node, and metas- addition, inhibition of DBC1 reduced the proliferation tasis staging system of the American Joint Committee and invasive potential of gastric cancer cells and squa- on Cancer [27]. Thereafter, the ovarian carcinomas mous cell carcinoma cells [12,20]. The decrease of tumor were grouped according to their age (<60 years versus ≥ invasiveness with inhibition of DBC1 was associated with 60 years), tumor stage (I and II versus III and IV), tumor a decrease in epithelial-mesenchymal transition (EMT) size (≤10 cm versus > 10 cm), lymph node metastasis (ab- signaling [12]. sence versus presence), presence of ascites (absence versus The role of DBC1 as a co-activator of hormone recep- presence), bilaterality (unilateral versus bilateral), presence tors raised the possibility that DBC1 could promote the of latent distant metastasis during follow-up (absence tumorigenesis of hormone-dependent organs [18,19,21]. versus presence), pre-operative serum level of CA19-9 In breast carcinoma, DBC1 is expected to be an indica- (normal versus elevated, reference value; 0 - 37 U/ml), tor of poor prognosis and might be involved in resist- pre-operative serum level of CA125 (normal versus ele- ance to the estrogen receptor-targeted therapies [14]. vated, reference value; 0 - 35 U/ml), and histologic grade However, there has been no study to date on the role of (low; grade 1 versus high; grade 2 and 3). The duration DBC1 in ovarian tumorigenesis, its relation to BRCA1/2, of follow-uprangedfromone to 193months(median; and the prognostic significance of DBC1 in ovarian can- 70 months). cers. Therefore, in this study, we evaluated the immuno- histochemical expression of DBC1 and BRCA1 and their Establishment of tissue microarray and prognostic significance in 104 ovarian carcinomas. immunohistochemical staining Tissue microarray (TMA) established from the most rep- Methods resentative solid area with highest histologic grade after Patients and tissue samples review of original H&E slides. One 5 mm tissue core per One hundred and four ovarian carcinomas diagnosed case was used for the construction of a TMA. Immunohis- between November 1996 and August 2008, and the ori- tochemical staining for DBC1 (1:100, Bethyl Laboratories, ginal histologic slides, tissue blocks, and clinical infor- Mongomery, TX) and BRCA1 (1:100, Abcam, Cambridge, mation were available were included in the present MA) was performed on 4 μm thick sections on TMA study. The age of the patients ranged from 21 to 82 years slides. The tissue sections underwent a microwave antigen (median; 54 years). All patients received staging opera- retrieval procedure in pH 6.0 sodium citrate buffer tions and 83 patients received platinum- and taxoid- for 20 minutes. Immunohistochemical analysis was per- based adjuvant chemotherapy. Among the 83 patients, formed by two pathologists (KYJ and KMK) by consensus, platinum-resistance was evaluable in 82 patients and 62 without knowledge of the clinicopathological information. patients were sensitive to platinum-based chemotherapy For the evaluation of the immunohistochemical staining Cho et al. Journal of Ovarian Research (2015) 8:2 Page 3 of 11 of DBC1 and BRCA1, the Allred nuclear scoring system Cox proportional hazard regression analysis. The associ- was used [28]. The staining intensity was scored as 0 (no ation between immunohistochemical positivity of DBC1 staining), 1 (weak staining), 2 (intermediate staining), or 3 expression and other clinicopathological factors poten- (strong staining). The area of staining was scored as 0 (no tially predictive of prognosis were analyzed using Pearson’s staining), 1 (1% of the cells stained positive), 2 (2-10% of chi-square test. SPSS software (version 20.0) was used the cells stained positive), 3 (11-33% of cells stained posi- throughout and P-values less than 0.05 were considered tive), 4 (34-66% of cells stained positive), or 5 (67-100% of statistically significant. cells stained positive). Thereafter, the sum score was ob- tained by adding the intensity score and staining area Results score [13,29], to give maximum sum score of eight and a Association of DBC1 and BRCA1 expression with minimum sum score of zero. clinicopathologic characteristics of ovarian carcinoma patients Statistical analysis As shown in Figure 1, DBC1 was expressed exclusively in The cut-off point of the immunohistochemical staining the nuclei of tumor cells and nuclear expression was eval- score for DBC1 and BRCA1 expression was determined uated for the evaluation of DBC1. BRCA1 was expressed by receiver operating characteristic curve analysis at the in both the cytoplasm and nuclei; however, we have evalu- highest positive likelihood ratio point for the event of ated only for the nuclear expression [30,31]. The asso- OS. The cut-off points for the sum score for DBC1 and ciations between the expression of DBC1, BRCA1, and BRCA1 were seven and six, respectively. The immuno- variable clinicopathologic features are summarized in staining for DBC1 was considered positive when the sum Table 1. Positive expression of DBC1 and BRCA1 were score was greater than or equal to seven and BRCA1 ex- seen in 63% (66/104) and 44% (46/104) of overall ovarian pression was considered positive when the sum score was carcinomas, respectively. Expression of DBC1 was signifi- greater than or equal to six. The endpoint of interest was cantly associated with higher tumor stage (P= 0.015), OS and relapse-free survival (RFS). The endpoint of bilateral tumors (P= 0.008), latent distant metastasis (P= follow-up was the date of last contact or date of death of 0.016), platinum-resistance (P= 0.016), higher pre-operative patients through August 2013. OS was calculated as the serum level of CA125 (P= 0.004), higher histologic grade time from the date of diagnosis to the date of last contact (P< 0.001), histologic type of ovarian carcinoma (P< or death from ovarian carcinomas. The patients who were 0.001), and BRCA1 expression (P< 0.001). DBC1 was alive at last contact were treated as censored for OS ana- expressed in 72% (54/75) of serous carcinoma and 100% lysis. RFS calculated from the date of diagnosis to the date of endometrioid carcinoma (5/5), clear cell carcinoma of last contact, local relapse, latent metastasis, or death (3/3), and the malignant Brenner tumor (1/1). How- from ovarian carcinomas. The patients who were alive at ever, only 15% (3/20) of mucinous carcinoma were last contact without experience of local relapse or latent positive for DBC1. BRCA1 expression was significantly metastasis were treated as censored for RFS analysis. associated with latent distant metastasis (P= 0.012), Survival analyses were performed according to the platinum-resistance (P= 0.014), and higher histologic Kaplan-Meier method, and univariate and multivariate grade (P = 0.007). Figure 1 Immunohistochemical expression of DBC1/CCAR2 and BRCA1 in ovarian carcinomas. DBC1/CCAR2 is primarily expressed in the nuclei of the tumor cells. BRCA1 is expressed both in the cytoplasm and nuclei of the tumor cells. Original magnification; ×400. Cho et al. Journal of Ovarian Research (2015) 8:2 Page 4 of 11 Table 1 Clinicopathological variables and the expression of DBC1 and BRCA1 in ovarian carcinomas Characteristics No. Overall ovarian car cinomas No. Serous c Arcinomas DBC1+ P BRCA1+ P DBC1+ P BRCA1+ P Age, y <60 71 41 (58%) 0.076 28 (39%) 0.149 45 29 (64%) 0.074 20 (44%) 0.450 ≥60 33 25 (76%) 18 (55%) 30 25 (83%) 16 (53%) Stage I & II 52 27 (52%) 0.015 21 (40%) 0.430 29 18 (62%) 0.128 13 (45%) 0.662 III & IV 52 39 (75%) 25 (48%) 46 36 (78%) 23 (50%) Tumor size, cm ≤10 68 48 (71%) 0.038 31 (46%) 0.702 56 40 (71%) 0.850 26 (46%) 0.64 >10 36 18 (50%) 15 (42%) 19 14 (74%) 10 (53%) LN metastasis Absence 84 50 (60%) 0.087 37 (44%) 0.939 56 39 (70%) 0.435 28 (50%) 0.552 Presence 20 16 (80%) 9 (45%) 19 15 (79%) 8 (42%) Ascites Absence 71 41 (58%) 0.076 28 (39%) 0.149 45 31 (69%) 0.462 18 (40%) 0.089 Presence 33 25 (76%) 18 (55%) 30 23 (77%) 18 (60%) Bilaterality Unilateral 59 31 (53%) 0.008 24 (41%) 0.404 34 21 (62%) 0.072 16 (47%) 0.882 Bilateral 45 35 (78%) 22 (49%) 41 33 (80%) 20 (49%) LD Meta Absence 76 43 (57%) 0.016 28 (37%) 0.012 52 34 (65%) 0.055 21 (40%) 0.047 Presence 28 23 (82%) 18 (64%) 23 20 (87%) 15 (65%) Platinum-resistance Absence 62 38 (61%) 0.016 21 (34%) 0.014 48 32 (67%) 0.008 19 (40%) 0.043 Presence 20 18 (90%) 13 (65%) 16 16 (100%) 11 (69%) CA19-9 Normal 66 47 (71%) 0.060 32 (48%) 0.158 50 39 (78%) 0.341 26 (52%) 0.156 Elevated 17 8 (47%) 5 (29%) 8 5 (63%) 2 925%) CA125 Normal 18 7 (39%) 0.004 5 (28%) 0.121 7 4 (57%) 0.249 4 (57%) 0.630 Elevated 75 56 (75%) 36 (48%) 61 47 (77%) 29 (48%) Histologic grade Low (1) 27 5 (19%) <0.001 6 (22%) 0.007 12 4 (33%) 0.001 4 (33%) 0.267 High (2 & 3) 77 61 (79%) 40 (52%) 63 50 (79%) 32 (51%) Histologic type Serous 75 54 (72%) <0.001 36 (48%) 0.254 Mucinous 20 3 (15%) 5 (25%) Endometrioid 5 5 (100%) 3 (60%) Clear cell 3 3 (100%) 1 (33%) Malignant Brenner 1 1 (100%) 1 (100%) BRCA1 Negative 58 28 (48%) <0.001 39 22 (56%) 0.002 Positive 46 38 (83%) 36 32 (89%) LN; lymph node, LD Meta; latent distant metastasis. The cases included in this study are heterogeneous. Expression of DBC1 and BRCA1 correlate with reduced Various histologic types of ovarian carcinomas with overall survival and relapse-free survival in ovarian different biologic and clinical background were included carcinomas by univariate analysis in this study. Thus, we did additional analysis accord- Univariate analysis for the OS and RFS of the variable ing to the histologic types, especially for the serous clinicopathological factors and DBC1 and BRCA1 expres- carcinoma. Among the 75 serous carcinomas, DBC1 sion in ovarian carcinomas are shown in Table 2. Among expression was significantly associated with higher histo- the 104 general cases of ovarian carcinoma, older age of logic grade (P = 0.001) and platinum-resistance (P= 0.008) the patients (OS; P <0.001, RFS; P = 0.003), higher tumor and showed a slight association of borderline signifi- stage (OS; P < 0.001, RFS; P < 0.001), presence of ascites cance with bilateral tumor (P= 0.072) and presence of (OS; P =0.006, RFS; P = 0.017), increased pre-operative latent distant metastasis (P= 0.055). BRCA1 expression serum level of CA125 (OS; P =0.013, RFS; P =0.004), was significantly associated with latent distant metas- histologic grade (OS; P = 0.005, RFS; P < 0.001), DBC1 tasis (P= 0.047) and platinum-resistance (P= 0.008) expression (Log-rank, OS; P <0.001, RFS; P < 0.001), and (Table 1). BRCA1 expression (Log-rank, OS; P =0.003, RFS; P = Cho et al. Journal of Ovarian Research (2015) 8:2 Page 5 of 11 Table 2 Univariate Cox regression analyses for overall survival and relapse-free survival in ovarian carcinomas Characteristics No. OS RFS HR (95% CI) P HR (95% CI) P Overall ovarian carcinomas (n = 104) Age, y, ≥ 60 (vs < 60) 33/104 2.686 (1.535-4.698) <0.001 2.157 (1.299-3.582) 0.003 Stage, III & IV (vs I & II) 52/104 3.579 (1.917-6.681) <0.001 3.930 (2.245-6.878) <0.001 Tumor size, cm, > 10 (vs ≤ 10) 36/104 0.524 (0.274-1.004) 0.051 0.649 (0.375-1.125) 0.123 LN metastasis, presence (vs absence) 20/104 1.568 (0.831-2.959) 0.165 1.889 (1.076-3.314) 0.027 Ascites, presence (vs absence) 33/104 1.997 (1.140-3.498) 0.016 1.854 (1.116-3.077) 0.017 Bilaterality, bilateral (vs unilateral) 45/104 1.647 (0.943-2.876) 0.080 1.995 (1.204-3.303) 0.007 CA19-9, elevated (vs normal) 17/83 0.753 (0.314-1.806) 0.525 0.811 (0.379-1.733) 0.588 CA125, elevated (vs normal) 75/93 4.451 (1.376-14.393) 0.013 4.458 (1.609-12.351) 0.004 Histologic grade, high (vs low) 77/104 3.762 (1.491-9.496) 0.005 3.794 (1.719-8.374) <0.001 DBC1, positive (vs negative) 66/104 3.474 (1.684-7.166) <0.001 3.007 (1.624-5.567) <0.001 BRCA1, positive (vs negative) 46/104 2.263 (1.287-3.979) 0.005 2.254 (1.359-3.739) 0.002 Serous carcinomas (n = 75) Age, y, ≥ 60 (vs < 60) 30/75 2.601 (1.411-4.796) 0.002 1.926 (1.116-3.323) 0.019 Stage, III & IV (vs I & II) 46/75 2.263 (1.131-4.528) 0.021 2.809 (1.485-5.312) 0.001 Tumor size, cm, > 10 (vs ≤ 10) 19/75 0.625 (0.289-1.352) 0.233 0.817 (0.436-1.532) 0.529 LN metastasis, presence (vs absence) 19/75 1.200 (0.613-2.349) 0.595 1.502 (0.831-2.714) 0.178 Ascites, presence (vs absence) 30/75 1.793 (0.977-3.291) 0.060 1.645 (0.953-2.839) 0.074 Bilaterality, bilateral (vs unilateral) 41/75 1.200 (0.647-2.224) 0.563 1.423 (0.813-2.492) 0.217 CA19-9, elevated (vs normal) 8/58 0.679 (0.206-2.236) 0.524 1.086 (0.425-2.773) 0.863 CA125, elevated (vs normal) 61/68 2.898 (0.697-12.056) 0.144 2.152 (0.668-6.931) 0.199 Histologic grade, high (vs low) 63/75 4.401 (1.061-18.260) 0.041 4.341 (1.347-13.990) 0.014 DBC1, positive (vs negative) 54/75 4.277 (1.674-10.926) 0.002 2.811 (1.363-5.794) 0.005 BRCA1, positive (vs negative) 36/75 1.861 (1.007-3.438) 0.047 1.792 (1.032-3.110) 0.038 High-grade serous carcinomas (n = 63) Age, y, ≥ 60 (vs < 60) 27/63 2.090 (1.119-3.900) 0.021 1.591 (0.907-2.791) 0.105 Stage, III & IV (vs I & II) 38/63 2.188 (1.080-4.434) 0.030 2.811 (1.464-5.399) 0.002 Tumor size, cm, > 10 (vs ≤ 10) 15/63 0.736 (0.339-1.599) 0.439 0.860 (0.448-1.651) 0.650 LN metastasis, presence (vs absence) 15/63 1.520 (0.766-3.017) 0.232 1.841 (0.992-3.417) 0.053 Ascites, presence (vs absence) 26/63 1.395 (0.749-2.598) 0.294 1.340 (0.764-2.351) 0.308 Bilaterality, bilateral (vs unilateral) 36/63 1.300 (0.683-2.475) 0.424 1.452 (0.809–2.603) 0.211 CA19-9, elevated (vs normal) 6/49 0.726 (0.220-2.403) 0.600 1.344 (0.521-3.467) 0.541 CA125, elevated (vs normal) 53/58 2.220 (0.531-9.276) 0.275 1.443 (0.446-4.672) 0.540 DBC1, positive (vs negative) 50/63 4.031 (1.427-11.382) 0.008 2.540 (1.135-5.684) 0.023 BRCA1, positive (vs negative) 32/63 2.010 (1.063-3.803) 0.032 1.719 (0.973-3.038) 0.062 0.003) were associated with shorter OS and RFS (Table 2) chemotherapy, DBC1 expression was significantly associ- (Figure 2). The patients with tumors expressing DBC1 ated with shorter OS (P = 0.004, hazard ration [HR]; 3.625, had a 3.474-fold (P< 0.001, 95% confidence interval [95% 95% CI; 1.518-8.656) and RFS (P = 0.004, HR; 2.738, 95% CI]; 1.684-7.166) greater risk of death and a 3.007-fold CI; 1.368-5.477). BRCA1 expression predicted shorter OS (P< 0.001, 95% CI; 1.624-5.567) greater risk of relapse (P = 0.005, HR; 2.263, 95% CI; 1.287-3.979) and RFS or death. The five- and ten-year OS rates of the DBC1- (P = 0.002, HR; 2.254, 95% CI; 1.359-3.739) (Table 2). negative group were 78% and 73%, respectively, and were When we did additional analysis in the subpopulation only 42% and 36% in DBC1-positive group, respectively. of serous carcinomas, the factors significantly associated In addition, among the 83 patients who received adjuvant with both OS and RFS by univariate analysis were the Cho et al. Journal of Ovarian Research (2015) 8:2 Page 6 of 11 Figure 2 Kaplan-Meier survival analyses in 104 overall ovarian carcinomas. Overall survival and relapse-free survival according to the tumor stage (A), histologic grade (B), DBC1 expression (C), and BRCA1 expression (D). Figure 3 Kaplan-Meier survival analyses in 75 ovarian serous carcinomas. Overall survival and relapse-free survival according to the tumor stage (A), histologic grade (B), DBC1 expression (C), and BRCA1 expression (D). Cho et al. Journal of Ovarian Research (2015) 8:2 Page 7 of 11 age of patients (OS; P = 0.002, RFS; P = 0.019), tumor and BRCA1 expression were significantly associated with stage (OS; P = 0.021, RFS; P = 0.001), histologic grade OS (Table 2) (Figure 4). The expression of DBC1 pre- (OS; P =0.041, RFS; P = 0.014), and DBC1 expression dicted a 4.031-fold (P= 0.008, 95% CI; 1.427-11.382) (Log-rank, OS; P <0.001, RFS; P = 0.003), and BRCA1 ex- greater risk of death and a 2.540-fold (P= 0.005, 95% CI; pression (Log-rank, OS; P =0.043, RFS; P =0.034) (Table 2) 1.135-5.684) greater risk of relapse or death of high- (Figure 3). The patients who had DBC1-expressing serous grade serous carcinoma patients (Table 2). The OS rates carcinoma had a 4.277-fold (P= 0.002, 95% CI; 1.674- at five- and ten-years of DBC1-negative high-grade ser- 10.926) greater risk of death and its expression was signifi- ous carcinomas were 85% and 64%, respectively, and cantly associated with shorter RFS (P= 0.005, HR; 2.811, were 36% and 25% in DBC1-positive high-grade serous 95% CI; 1.363-5.794) (Figure 3C). carcinomas. Among the 63 high-grade serous carcinomas, tumor In the 20 cases of mucinous carcinomas, tumor stage stage and the expression of DBC1 were significantly as- was significantly associated with shorter OS (Log-rank, P< sociated with both OS and RFS, and the age of patients 0.001) and RFS (Log-rank, P< 0.001). DBC1 expression Figure 4 Kaplan-Meier survival analyses in 63 high-grade serous carcinomas. Overall survival and relapse-free survival according to the tumor stage (A), DBC1 expression (B), and BRCA1 expression (C). Cho et al. Journal of Ovarian Research (2015) 8:2 Page 8 of 11 showed borderline significancefor thepredictionofOSof and histologic grade (P= 0.009) (Table 3). In addition, the mucinous carcinoma patients (Log-rank, P= 0.060). age of the patients (P = 0.035) and the expression of DBC1 (P = 0.011) were the independent predictor of OS in Expression of DBC1 is an independent prognostic high-grade serous carcinomas. The expression of DBC1 indicator of worse survival outcome in ovarian predicted a 3.828-fold (95% CI, 1.353-10.827) greater risk carcinomas by multivariate analysis of death of high-grade serous carcinoma patients (Table 3). The factors significantly associated with OS or RFS by univariate analysis were included in the multivariate ana- Discussion lysis. Because of data for CA125 was missing in 11 patients, This study has shown that immunohistochemical ex- the CA125 level was not included in the multivariate ana- pression of DBC1 was significantly associated with ad- lysis. The factors included in the multivariate analysis of vanced clinicopathological factors of ovarian carcinoma OS and RFS were age, tumor stage, lymph node metasta- such as higher tumor stage, latent distant metastasis, sis, presence of ascites, bilaterality of the tumor, histologic platinum-resistance, elevated serum level of CA125, and grade, BRCA1 expression, and DBC1 expression. In 104 higher histologic grade. Moreover, DBC1 expression was ovarian carcinomas, the factors significantly associated significantly associated with shorter survival of ovarian with OS by multivariate analysis were age (P =0.010), carcinomas, especially in high-grade serous carcinomas. In tumor stage (P = 0.006), and DBC1 expression (P =0.021). agreement with our results, increased expression of DBC1 The patients with tumors expressing DBC1 had a 2.423 has been reported as an indicator of poor prognosis of fold (95% CI, 1.144-5.132) greater risk of death (Table 3). gastric carcinoma [15], breast carcinoma [14], colorectal Tumor stage (P< 0.001) and histologic grade (P= 0.007) carcinoma [9], esophageal carcinoma [20], clear cell renal were the independent predictor of RFS. In addition, DBC1 cell carcinoma [12], diffuse large B cell lymphoma [13], expression was an independent predictor of OS (P =0.026, and soft tissue sarcomas [13]. Nevertheless, there has been HR; 2.735, 95% CI; 1.128-6.634) among the 83 patients no report investigating DBC1 expression in ovarian car- who received adjuvant chemotherapy, as indicated by cinomas. Therefore, this is the first report that examined multivariate analysis. DBC1 expression in human ovarian tumors and suggests In the subpopulation of 75 serous carcinomas, the age of that DBC1 expression might be usable as a prognostic in- the patients (P = 0.010) and DBC1 expression (P =0.006) dicator for ovarian carcinoma patients. were the independent predictors of OS. The expression of DBC1 is interesting because of its putative role for the DBC1 predicted a 3.757-fold (95% CI, 1.462-9.653) greater inhibition of SIRT1 and has been suggested as tumor sup- risk of death. The factors significantly associated with pressor [4,16,32]. However, there have been conflicting re- RFS in serous carcinoma were tumor stage (P< 0.001) ports regarding the role of DBC1 and SIRT1 in human Table 3 Multivariate Cox regression analyses for overall survival and relapse-free survival in ovarian carcinomas Characteristics OS RFS HR (95% CI) P HR (95% CI) P Overall ovarian carcinomas Age, y, ≥ 60 (vs < 60) 2.100 (1.191-3.702) 0.010 Stage, III & IV (vs I & II) 2.488 (1.295-4.780) 0.006 3.426 (1.944-6.036) <0.001 Histologic grade, high (vs low) 3.023 (1.355-6.742) 0.007 DBC1, positive (vs negative) 2.423 (1.144-5.132) 0.021 Serous carcinomas Age, y, ≥ 60 (vs < 60) 2.241 (1.212-4.144) 0.010 Stage, III & IV (vs I & II) 3.023 (1.588-5.755) <0.001 Histologic grade, high (vs low) 4.818 (1.487-15.614) 0.009 DBC1, positive (vs negative) 3.757 (1.462-9.653) 0.006 High-grade serous carcinomas Age, y, ≥ 60 (vs < 60) 1.961 (1.050-3.664) 0.035 Stage, III & IV (vs I & II) 2.488 (1.280-4.836) 0.007 DBC1, positive (vs negative) 3.828 (1.353-10.827) 0.011 2.059 (0.907-4.677) 0.084 The variables included in the multivariate analysis were age, tumor stage, lymph node metastasis, presence of ascites, bilaterality of the tumor, histologic grade, BRCA1 expression, and DBC1 expression. The variables included in the multivariate analysis were age, tumor stage, histologic grade, BRCA1 expression, and DBC1 expression. The variables included in the multivariate analysis were age, tumor stage, BRCA1 expression, and DBC1 expression. Cho et al. Journal of Ovarian Research (2015) 8:2 Page 9 of 11 cancers. SIRT1-induced expression of various oncogenes The higher rate of distant metastatic relapse in DBC1- and formed a positive-feedback loop with the c-Myc onco- expressing ovarian carcinomas raises the possibility that gene to stimulate tumorigenesis [33,34]. However, SIRT1 DBC1 might be involved in the acquisition of resistance formed a negative-feedback loop with the c-Myc oncogene for the postoperative chemotherapies. Among the 83 ovar- in another report [35]. Moreover, the effects of the expres- ian carcinoma patients who received adjuvant chemother- sion of DBC1 and SIRT1 in human malignant tumors var- apy, the expression of DBC1 predicted shorter OS and ied according to cell type [6,9,34,36,37]. The expression of RFS. In addition, among the 55 high-grade serous carcin- both DBC1 and SIRT1 predicted shorter survival of gastric oma patients who received adjuvant chemotherapy, DBC1 carcinoma [15], breast carcinoma [14], clear cell renal cell expression was significantly associated with poor OS (P = carcinoma [12], soft-tissue sarcoma [13], and diffuse large 014, HR; 4.484, 95% CI; 1.362-14.758) and RFS (P =0.042, B cell lymphoma [13,16]. In colon cancer, DBC1 was over- HR; 2.471, 95% CI; 1.035-5.899). Moreover, DBC1 ex- expressed in colorectal cancer and predicted shorter pression correlated with platinum-resistance. All serous survival of patients [9]. In contrast, another study reported carcinoma patients having tumors with DBC1 expression that SIRT1 expression is associated with poor prognosis (100%, 16/16) showed platinum-resistance. In contrast, but DBC1 expression is associated with favorable progno- 62% (32/48) of DBC1-negative serous carcinoma patients sis of gastric cancer patients [36]. Although the expression showed platinum-resistance. Similarly, DBC1 expression of SIRT1 was higher in ovarian carcinomas compared was associated with frequent relapse and shorter survival with benign and borderline ovarian tumors, SIRT1 ex- of breast carcinoma patients who received adjuvant chemo- pression was associated favorable prognosis of ovarian therapy [14]. Although it did not reach statistical sig- carcinoma patients [38]. Therefore, poor prognosis of nificance, lower expression of DBC1 would indicate a DBC1-expressing ovarian carcinoma might be related favorable pathological response to chemotherapy [39]. to its inhibitory role for SIRT1. However, the relationship Because DBC1 is involved in the inhibition of BRCA1 between DBC1 and SIRT1 was been frequently dissociated [22] and BRCA1/2 status is important in the develop- as shown in breast cancer [6]. Moreover, the knock-down ment and progression of ovarian carcinomas, we investi- of DBC1 inhibited proliferation of liver cancer cells [37] gated the immunohistochemical expression of BRCA1 in and suppressed invasiveness of gastric cancer cells [12]. ovarian carcinomas. Although we could evaluate the im- Therefore, it may be likely that DBC1 has its own role munohistochemical expression of BRCA1, a recent report in tumorigenesis. DBC1 regulates BRCA1-mediated has shown that there is a strong correlation between the function by binding to the BRCT domain in addition to immunohistochemical expression and molecular events in the suppression of SIRT1 expression [22]. In addition, BRCA1 [30]. In this study, BRCA1 expression was signifi- DBC1 inhibits senescence of premalignant cells by dis- cantly associated with latent distant metastasis, platinum- rupting the SUV39H1-SIRT1 complex. However, DBC1 resistance, and higher histologic grade. In addition, in showed a co-inhibitory effect for SUV39H1 and SIRT1 agreement with previous reports [24,40,41], we have dem- [8]. Therefore, there is a possibility that DBC1 may have onstrated that low-expression of BRCA1 is associated with both tumorigenic and anti-tumorigenic roles [8,22]. Thus, poor survival of ovarian carcinomas. The reason why the further study is needed to explore the exact role of DBC1 patients with defective BRCA1/2 have a longer survival in tumorigenesis. times compared with BRCA1/2 wild-type carcinomas is Because the expression of DBC1 was positively corre- related with BRCA1/2-defects in cells making them more lated with higher tumor stage, higher tumor grade, and sensitive to conventional chemotherapy, especially to latent metastasis of ovarian carcinoma, there is a possi- the platinum-based chemotherapy [23,24,42]. Our re- bility that DBC1 might be involved in the acquisition of sults have also shown that BRCA1-positivity is significantly invasive and metastatic potential. Recently, it has been associated with increased platinum-resistance (Table 1). Thereby, several therapeutic applications according to the shown that DBC1 is associated with the invasive potential of esophageal squamous cell carcinoma [20] and is im- BRCA1/2 status are under evaluation. Recently, PARP in- portant in the EMT of gastric carcinoma cells [12]. Espe- hibitors have been reported as being specifically applicable to the treatment of BRCA1/2-defective cancers [43,44]. In cially, the oncogenic role of DBC1 was regulated by the kinase effect of CK2α.CK2α phosphorylates DBC1 and our study, the expression of DBC1 and BRCA1 showed that is important for the induction of EMT. Knockdown positive correlation and the expressions of both molecules was related with platinum-resistance and shorter survival of DBC1 inhibited invasiveness of gastric cancer cells and a point mutation at the phosphorylation site of DBC1 de- of ovarian carcinoma patients. Based on the inhibitory role creased the expression of MMP2, MMP9, snail, smad3, of DBC1 for the BRCA1 [22], the co-expressing pattern of and N-cadherin [12]. In addition, DBC1 induced anoikis these two molecules in the poor prognostic group of resistance that is important in tumor metastasis by activat- ovarian carcinomas is questionable and paradoxical as ing the NFkB signaling pathway in breast cancer [17]. BRCA1/2 defective cancers are more susceptible to therapy Cho et al. Journal of Ovarian Research (2015) 8:2 Page 10 of 11 [23,24,42]. This phenomenon might be related with the diverse carcinomas and its expression is predictive of prognosis roles of DBC1 in tumorigenesis and further study is needed. of ovarian carcinoma patients, especially in high-grade Another possible oncogenic role of DBC1 might be re- serous carcinomas and possibly in mucinous carcinomas. lated with its role in the co-activation of nuclear recep- In addition, DBC1 expression was significantly associated tors [18,19,21]. DBC1 co-activates estrogen receptor and with BRCA1 expression and their expressions were related androgen receptor (AR), which can be ligand-dependent with resistance to platinum-based chemotherapy and poor or ligand-independent [18,19,21]. Although there was no prognosis of ovarian carcinoma patients. Therefore, these significant correlation between the expression of DBC1 results indicate that the expression of DBC1 and BRCA1 and estrogen receptor in breast carcinoma [14], signifi- might be used for the prediction of prognosis of ovarian cant positive correlations between the expression of carcinomas. Especially, DBC1 expression might be helpful DBC1 and AR have been reported in clear cell renal cell for the prediction of the prognosis of high-grade serous carcinoma [12] and diffuse large B cell lymphoma [11]. carcinomas. In addition, these findings suggest that DBC1 Especially, the expression of both DBC1 and AR pre- and BRCA1could be potential therapeutic targets for the dicted shorter survival of cancer patients [11,12,14-16]. treatment of ovarian carcinomas according to the expres- Additionally, ovarian epithelium expressing AR and an- sion status of DBC1 and BRCA1. However, because of the drogen induced proliferation of ovarian epithelial cells limited number of non-serous cases of ovarian carcinoma and inhibited cell death [45]. In ovarian high-grade ser- subtypes in this study, further study with more cases is ous carcinomas, immunohistochemical expression of AR needed to clarify the roles of DBC1 and BRCA1 in various correlated with the S-phase fraction and AR expression histologic subtypes of ovarian carcinomas. decreased with platinum-based chemotherapy [46]. These Abbreviations reports suggest that AR is involved in the ovarian carcino- AR: Androgen receptor; CCAR2: Cell cycle and apoptosis regulator 2; genesis. Therefore, there is a possibility that DBC1 is in- CI: Confidence interval; DBC1: Deleted in breast cancer 1; EMT: Epithelial- mesenchymal transition; HR: Hazard ration; LN: Lymph node; OS: Overall volved in ovarian tumorigenesis with the interaction with survival; RFS: Relapse-free survival; TMA: Tissue microarray. AR and further study is needed. Ovarian carcinomas are a heterogeneous group of can- Competing interests The authors declare that they have no competing interests. cers that have origins and pathogenic profiles that differ according to histologic types. Therefore, when we con- Authors’ contributions sider the prognostic impact of DBC1 expression according DHJ, HSP, SHP, KMK, MJC, WSM, MJK, and KYJ participated in the study to histologic types of ovarian carcinoma, DBC1 predicted design. DHJ and SHP did the immunohistochemical staining. DHJ, SHP, KMK, MJC, WSM, MJK, and KYJ were involved in data collection and data interpretation. DHJ, shorter survival in serous carcinomas, especially in high- HSP, KMK, and KYJ participated in the statistical analysis. DHJ, HSP, SHP, KMK, grade serous carcinomas. The 10-years OS rate was only MJC, WSM, MJK, and KYJ wrote the manuscript. All authors read and approved 25% in DBC1-positive cases, and was 64% in DBC1- the final manuscript. negative cases. In mucinous carcinomas, DBC1 expression Acknowledgements was very low compared with other subtypes of ovarian This paper was supported by Research Funds of Chonbuk National University carcinomas (15% in mucinous carcinoma, 72% in serous in and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2008-0062279). We thank DB Leveson-Gower carcinoma, and 100% in endometrioid carcinoma). How- who provided medical writing services. ever, despite the low frequency of DBC1-positivity and the small number of cases of mucinous carcinoma, DBC1 Author details Department of Obstetrics and Gynecology, Chonbuk National University expression showed borderline significance in OS analysis Medical School and Research Institute of Clinical Medicine, Jeonju, Republic (Log-rank, P = 0.060). The 10-years OS rates of DBC1- of Korea. Departments of Pathology, Chonbuk National University Medical negative and DBC1-positive mucinous carcinomas were School, Research Institute of Clinical Medicine and Research Institute for Endocrine Sciences, Jeonju, Republic of Korea. Division of Gynecologic 76% and 33%, respectively. In line with our results, DBC1 Oncology, Department of Obstetrics and Gynecology, Stanford University expression was associated with a higher nuclear grade of School of Medicine, Stanford, California, USA. breast carcinoma [39]. 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The expression of DBC1/CCAR2 is associated with poor prognosis of ovarian carcinoma

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Springer Journals
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Copyright © 2015 by Cho et al.; licensee BioMed Central.
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Medicine & Public Health; Gynecology; Reproductive Medicine
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1757-2215
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10.1186/s13048-015-0129-3
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25823848
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Abstract

Background: Recent reports have shown that deleted in breast cancer 1 (DBC1/CCAR2) is an indicator of poor prognosis of various human cancers. However, its expression in ovarian carcinoma has not been reported. Methods: We investigated the immunohistochemical expression of DBC1 and BRCA1 and their prognostic significance in 104 ovarian carcinomas. Survival analyses were performed according to the Kaplan-Meier method, as well as univariate and multivariate Cox proportional hazard regression analysis. Results: Positive expression of DBC1 and BRCA1 were seen in 63% (66/104) and 44% (46/104) of overall ovarian carcinomas, respectively. DBC1 expression was significantly associated with advanced clinicopathological factors such as high tumor stage, latent distant metastasis, platinum-resistance, elevated serum levels of CA125, high histologic grade, and BRCA1 expression. In the histological subtypes of ovarian carcinomas, DBC1 expression was more common in serous carcinoma (72%, 54/75) than mucinous carcinoma (15%, 3/20). BRCA1 expression was significantly associated with latent distant metastasis, platinum-resistance, and higher histologic grade. In addition, DBC1 expression was significantly associated with shorter overall survival (OS) and relapse-free survival (RFS) in 104 ovarian carcinomas (OS; P < 0.001, RFS; P < 0.001) and 63 high-grade serous carcinomas (OS; P = 0.008, RFS; P = 0.023) by univariate analysis. BRCA1 expression was significantly associated with OS and RFS in 104 ovarian carcinomas (OS; P = 0.005, RFS; P =0.002) and 75 serous carcinomas (OS; P = 0.047, RFS; P = 0.038) by univariate analysis. Moreover, DBC1 expression was an independent prognostic indicator for OS in both 104 ovarian carcinomas (P= 0.021) and 63 high-grade serous carcinomas (P= 0.011) by multivariate analysis. Conclusions: These results indicate that the expression of DBC1 and BRCA1 are closely related with in the progression of ovarian carcinomas and may have clinical utility in the prediction of prognosis of ovarian carcinomas. Especially, DBC1 expression could be employed as a significant prognostic indicator for ovarian carcinomas especially in high-grade serous carcinomas. Keywords: Ovarian neoplasms, Serous carcinoma, Deleted in breast cancer 1, BRCA1, Prognosis Background suppressor [1]. Based on data of cBio Cancer Genomics Deleted in breast cancer 1/cell cycle and apoptosis regu- Portal (http://www.cbioportal.org), the deletion of DBC1 lator 2 (DBC1/CCAR2) was named by its deletion at a has been reported in 2.5% (8/316) to 7.7% (24/311) of region 8p22 in breast cancer. Thereafter, DBC1 was re- ovarian serous carcinomas [2,3]. Especially, the inhibitory designated CCAR2 to eliminate possible confusion with role of DBC1 on SIRT1 supported the possibility that deleted in bladder cancer 1 and because it has partial se- DBC1 could be tumor suppressor because SIRT1 inacti- quence homology to CCAR1. The deletion of DBC1 in vates various tumor suppressors, especially p53 [4,5]. How- breast cancer suggested it may have a role as a tumor ever, these findings were followed by conflicting reports, which cast doubt on whether DBC1 is tumor suppressor. * Correspondence: kyjang@chonbuk.ac.kr In human cancers, the deletion of DBC1 was not a com- Departments of Pathology, Chonbuk National University Medical School, mon phenomenon and the balance between SIRT1 and Research Institute of Clinical Medicine and Research Institute for Endocrine DBC1 was disrupted in human cancers [6]. When the Sciences, Jeonju, Republic of Korea Full list of author information is available at the end of the article © 2015 Cho et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cho et al. Journal of Ovarian Research (2015) 8:2 Page 2 of 11 interaction between SIRT1 and DBC1 is week, the de- and 20 patients showed platinum-resistance. Platinum- pletion of DBC1 makes cells susceptible to UV-induced resistance was evaluated according to the standard genotoxic stress [7]. Also, DBC1 inhibits senescence of Gynecologic Oncology Group criteria [25]. The patients premalignant cells by disrupting the SUV39H1-SIRT1 who experienced recurrence or progression of ovarian complex [8]. Moreover, the expression of both DBC1 and cancer within the six months of platinum-based chemo- SIRT1 were correlated with advanced clinicopathological therapy were included in platinum-resistant group. Among characteristics and poor prognosis of human malignant tu- the 104 ovarian carcinoma patients, 39 patients experi- mors [9-16]. In addition, it has been shown that DBC1 has enced relapse and 50 patients died from ovarian carcinoma multiple functions involved in the regulation of cell survival, at the endpoint of follow-up. The five- and ten-year overall energy metabolism, and intracellular signal transduction survival (OS) rates were 57% and 50%, respectively. This [8,12,17-21]. Therefore, DBC1 might have its own role in study was approved by the institutional review board of tumorigenesis in addition to an inhibitory role for SIRT1. Chonbuk National University Hospital. Informed consent The tumorigenic role of DBC1, although controversial, was provided according to the Declaration of Helsinki. is supported by its role in the inhibition of tumor sup- All histologic slides and clinicopathologic factors were pressors [8,22] and activation of nuclear receptors with reviewed according to the criteria of the World Health tumorigenic potential [21]. DBC1 inhibits the tumor Organization classification of tumors of female repro- suppressor BRCA1 by binding to the BRCT domain in ductive organs [26]. The ovarian carcinomas included in breast cancer [22]. Defect of BRCA1/2 is involved in the this study, according to the histologic types, were 75 ser- development of ovarian carcinomas and defects in ous carcinomas (12 low-grade serous carcinomas and 63 BRCA1/2 are associated with the resistance to platinum- high-grade serous carcinomas), 20 mucinous carcinomas, based chemotherapy in ovarian carcinomas [23,24]. There- 5 endometrioid carcinomas, 3 clear cell carcinomas, and fore, there is a possibility that DBC1 may be involved in one malignant Brenner tumor. Tumor stage was reviewed BRCA1/2-related progression of ovarian carcinomas. In according to the guidelines of the tumor, node, and metas- addition, inhibition of DBC1 reduced the proliferation tasis staging system of the American Joint Committee and invasive potential of gastric cancer cells and squa- on Cancer [27]. Thereafter, the ovarian carcinomas mous cell carcinoma cells [12,20]. The decrease of tumor were grouped according to their age (<60 years versus ≥ invasiveness with inhibition of DBC1 was associated with 60 years), tumor stage (I and II versus III and IV), tumor a decrease in epithelial-mesenchymal transition (EMT) size (≤10 cm versus > 10 cm), lymph node metastasis (ab- signaling [12]. sence versus presence), presence of ascites (absence versus The role of DBC1 as a co-activator of hormone recep- presence), bilaterality (unilateral versus bilateral), presence tors raised the possibility that DBC1 could promote the of latent distant metastasis during follow-up (absence tumorigenesis of hormone-dependent organs [18,19,21]. versus presence), pre-operative serum level of CA19-9 In breast carcinoma, DBC1 is expected to be an indica- (normal versus elevated, reference value; 0 - 37 U/ml), tor of poor prognosis and might be involved in resist- pre-operative serum level of CA125 (normal versus ele- ance to the estrogen receptor-targeted therapies [14]. vated, reference value; 0 - 35 U/ml), and histologic grade However, there has been no study to date on the role of (low; grade 1 versus high; grade 2 and 3). The duration DBC1 in ovarian tumorigenesis, its relation to BRCA1/2, of follow-uprangedfromone to 193months(median; and the prognostic significance of DBC1 in ovarian can- 70 months). cers. Therefore, in this study, we evaluated the immuno- histochemical expression of DBC1 and BRCA1 and their Establishment of tissue microarray and prognostic significance in 104 ovarian carcinomas. immunohistochemical staining Tissue microarray (TMA) established from the most rep- Methods resentative solid area with highest histologic grade after Patients and tissue samples review of original H&E slides. One 5 mm tissue core per One hundred and four ovarian carcinomas diagnosed case was used for the construction of a TMA. Immunohis- between November 1996 and August 2008, and the ori- tochemical staining for DBC1 (1:100, Bethyl Laboratories, ginal histologic slides, tissue blocks, and clinical infor- Mongomery, TX) and BRCA1 (1:100, Abcam, Cambridge, mation were available were included in the present MA) was performed on 4 μm thick sections on TMA study. The age of the patients ranged from 21 to 82 years slides. The tissue sections underwent a microwave antigen (median; 54 years). All patients received staging opera- retrieval procedure in pH 6.0 sodium citrate buffer tions and 83 patients received platinum- and taxoid- for 20 minutes. Immunohistochemical analysis was per- based adjuvant chemotherapy. Among the 83 patients, formed by two pathologists (KYJ and KMK) by consensus, platinum-resistance was evaluable in 82 patients and 62 without knowledge of the clinicopathological information. patients were sensitive to platinum-based chemotherapy For the evaluation of the immunohistochemical staining Cho et al. Journal of Ovarian Research (2015) 8:2 Page 3 of 11 of DBC1 and BRCA1, the Allred nuclear scoring system Cox proportional hazard regression analysis. The associ- was used [28]. The staining intensity was scored as 0 (no ation between immunohistochemical positivity of DBC1 staining), 1 (weak staining), 2 (intermediate staining), or 3 expression and other clinicopathological factors poten- (strong staining). The area of staining was scored as 0 (no tially predictive of prognosis were analyzed using Pearson’s staining), 1 (1% of the cells stained positive), 2 (2-10% of chi-square test. SPSS software (version 20.0) was used the cells stained positive), 3 (11-33% of cells stained posi- throughout and P-values less than 0.05 were considered tive), 4 (34-66% of cells stained positive), or 5 (67-100% of statistically significant. cells stained positive). Thereafter, the sum score was ob- tained by adding the intensity score and staining area Results score [13,29], to give maximum sum score of eight and a Association of DBC1 and BRCA1 expression with minimum sum score of zero. clinicopathologic characteristics of ovarian carcinoma patients Statistical analysis As shown in Figure 1, DBC1 was expressed exclusively in The cut-off point of the immunohistochemical staining the nuclei of tumor cells and nuclear expression was eval- score for DBC1 and BRCA1 expression was determined uated for the evaluation of DBC1. BRCA1 was expressed by receiver operating characteristic curve analysis at the in both the cytoplasm and nuclei; however, we have evalu- highest positive likelihood ratio point for the event of ated only for the nuclear expression [30,31]. The asso- OS. The cut-off points for the sum score for DBC1 and ciations between the expression of DBC1, BRCA1, and BRCA1 were seven and six, respectively. The immuno- variable clinicopathologic features are summarized in staining for DBC1 was considered positive when the sum Table 1. Positive expression of DBC1 and BRCA1 were score was greater than or equal to seven and BRCA1 ex- seen in 63% (66/104) and 44% (46/104) of overall ovarian pression was considered positive when the sum score was carcinomas, respectively. Expression of DBC1 was signifi- greater than or equal to six. The endpoint of interest was cantly associated with higher tumor stage (P= 0.015), OS and relapse-free survival (RFS). The endpoint of bilateral tumors (P= 0.008), latent distant metastasis (P= follow-up was the date of last contact or date of death of 0.016), platinum-resistance (P= 0.016), higher pre-operative patients through August 2013. OS was calculated as the serum level of CA125 (P= 0.004), higher histologic grade time from the date of diagnosis to the date of last contact (P< 0.001), histologic type of ovarian carcinoma (P< or death from ovarian carcinomas. The patients who were 0.001), and BRCA1 expression (P< 0.001). DBC1 was alive at last contact were treated as censored for OS ana- expressed in 72% (54/75) of serous carcinoma and 100% lysis. RFS calculated from the date of diagnosis to the date of endometrioid carcinoma (5/5), clear cell carcinoma of last contact, local relapse, latent metastasis, or death (3/3), and the malignant Brenner tumor (1/1). How- from ovarian carcinomas. The patients who were alive at ever, only 15% (3/20) of mucinous carcinoma were last contact without experience of local relapse or latent positive for DBC1. BRCA1 expression was significantly metastasis were treated as censored for RFS analysis. associated with latent distant metastasis (P= 0.012), Survival analyses were performed according to the platinum-resistance (P= 0.014), and higher histologic Kaplan-Meier method, and univariate and multivariate grade (P = 0.007). Figure 1 Immunohistochemical expression of DBC1/CCAR2 and BRCA1 in ovarian carcinomas. DBC1/CCAR2 is primarily expressed in the nuclei of the tumor cells. BRCA1 is expressed both in the cytoplasm and nuclei of the tumor cells. Original magnification; ×400. Cho et al. Journal of Ovarian Research (2015) 8:2 Page 4 of 11 Table 1 Clinicopathological variables and the expression of DBC1 and BRCA1 in ovarian carcinomas Characteristics No. Overall ovarian car cinomas No. Serous c Arcinomas DBC1+ P BRCA1+ P DBC1+ P BRCA1+ P Age, y <60 71 41 (58%) 0.076 28 (39%) 0.149 45 29 (64%) 0.074 20 (44%) 0.450 ≥60 33 25 (76%) 18 (55%) 30 25 (83%) 16 (53%) Stage I & II 52 27 (52%) 0.015 21 (40%) 0.430 29 18 (62%) 0.128 13 (45%) 0.662 III & IV 52 39 (75%) 25 (48%) 46 36 (78%) 23 (50%) Tumor size, cm ≤10 68 48 (71%) 0.038 31 (46%) 0.702 56 40 (71%) 0.850 26 (46%) 0.64 >10 36 18 (50%) 15 (42%) 19 14 (74%) 10 (53%) LN metastasis Absence 84 50 (60%) 0.087 37 (44%) 0.939 56 39 (70%) 0.435 28 (50%) 0.552 Presence 20 16 (80%) 9 (45%) 19 15 (79%) 8 (42%) Ascites Absence 71 41 (58%) 0.076 28 (39%) 0.149 45 31 (69%) 0.462 18 (40%) 0.089 Presence 33 25 (76%) 18 (55%) 30 23 (77%) 18 (60%) Bilaterality Unilateral 59 31 (53%) 0.008 24 (41%) 0.404 34 21 (62%) 0.072 16 (47%) 0.882 Bilateral 45 35 (78%) 22 (49%) 41 33 (80%) 20 (49%) LD Meta Absence 76 43 (57%) 0.016 28 (37%) 0.012 52 34 (65%) 0.055 21 (40%) 0.047 Presence 28 23 (82%) 18 (64%) 23 20 (87%) 15 (65%) Platinum-resistance Absence 62 38 (61%) 0.016 21 (34%) 0.014 48 32 (67%) 0.008 19 (40%) 0.043 Presence 20 18 (90%) 13 (65%) 16 16 (100%) 11 (69%) CA19-9 Normal 66 47 (71%) 0.060 32 (48%) 0.158 50 39 (78%) 0.341 26 (52%) 0.156 Elevated 17 8 (47%) 5 (29%) 8 5 (63%) 2 925%) CA125 Normal 18 7 (39%) 0.004 5 (28%) 0.121 7 4 (57%) 0.249 4 (57%) 0.630 Elevated 75 56 (75%) 36 (48%) 61 47 (77%) 29 (48%) Histologic grade Low (1) 27 5 (19%) <0.001 6 (22%) 0.007 12 4 (33%) 0.001 4 (33%) 0.267 High (2 & 3) 77 61 (79%) 40 (52%) 63 50 (79%) 32 (51%) Histologic type Serous 75 54 (72%) <0.001 36 (48%) 0.254 Mucinous 20 3 (15%) 5 (25%) Endometrioid 5 5 (100%) 3 (60%) Clear cell 3 3 (100%) 1 (33%) Malignant Brenner 1 1 (100%) 1 (100%) BRCA1 Negative 58 28 (48%) <0.001 39 22 (56%) 0.002 Positive 46 38 (83%) 36 32 (89%) LN; lymph node, LD Meta; latent distant metastasis. The cases included in this study are heterogeneous. Expression of DBC1 and BRCA1 correlate with reduced Various histologic types of ovarian carcinomas with overall survival and relapse-free survival in ovarian different biologic and clinical background were included carcinomas by univariate analysis in this study. Thus, we did additional analysis accord- Univariate analysis for the OS and RFS of the variable ing to the histologic types, especially for the serous clinicopathological factors and DBC1 and BRCA1 expres- carcinoma. Among the 75 serous carcinomas, DBC1 sion in ovarian carcinomas are shown in Table 2. Among expression was significantly associated with higher histo- the 104 general cases of ovarian carcinoma, older age of logic grade (P = 0.001) and platinum-resistance (P= 0.008) the patients (OS; P <0.001, RFS; P = 0.003), higher tumor and showed a slight association of borderline signifi- stage (OS; P < 0.001, RFS; P < 0.001), presence of ascites cance with bilateral tumor (P= 0.072) and presence of (OS; P =0.006, RFS; P = 0.017), increased pre-operative latent distant metastasis (P= 0.055). BRCA1 expression serum level of CA125 (OS; P =0.013, RFS; P =0.004), was significantly associated with latent distant metas- histologic grade (OS; P = 0.005, RFS; P < 0.001), DBC1 tasis (P= 0.047) and platinum-resistance (P= 0.008) expression (Log-rank, OS; P <0.001, RFS; P < 0.001), and (Table 1). BRCA1 expression (Log-rank, OS; P =0.003, RFS; P = Cho et al. Journal of Ovarian Research (2015) 8:2 Page 5 of 11 Table 2 Univariate Cox regression analyses for overall survival and relapse-free survival in ovarian carcinomas Characteristics No. OS RFS HR (95% CI) P HR (95% CI) P Overall ovarian carcinomas (n = 104) Age, y, ≥ 60 (vs < 60) 33/104 2.686 (1.535-4.698) <0.001 2.157 (1.299-3.582) 0.003 Stage, III & IV (vs I & II) 52/104 3.579 (1.917-6.681) <0.001 3.930 (2.245-6.878) <0.001 Tumor size, cm, > 10 (vs ≤ 10) 36/104 0.524 (0.274-1.004) 0.051 0.649 (0.375-1.125) 0.123 LN metastasis, presence (vs absence) 20/104 1.568 (0.831-2.959) 0.165 1.889 (1.076-3.314) 0.027 Ascites, presence (vs absence) 33/104 1.997 (1.140-3.498) 0.016 1.854 (1.116-3.077) 0.017 Bilaterality, bilateral (vs unilateral) 45/104 1.647 (0.943-2.876) 0.080 1.995 (1.204-3.303) 0.007 CA19-9, elevated (vs normal) 17/83 0.753 (0.314-1.806) 0.525 0.811 (0.379-1.733) 0.588 CA125, elevated (vs normal) 75/93 4.451 (1.376-14.393) 0.013 4.458 (1.609-12.351) 0.004 Histologic grade, high (vs low) 77/104 3.762 (1.491-9.496) 0.005 3.794 (1.719-8.374) <0.001 DBC1, positive (vs negative) 66/104 3.474 (1.684-7.166) <0.001 3.007 (1.624-5.567) <0.001 BRCA1, positive (vs negative) 46/104 2.263 (1.287-3.979) 0.005 2.254 (1.359-3.739) 0.002 Serous carcinomas (n = 75) Age, y, ≥ 60 (vs < 60) 30/75 2.601 (1.411-4.796) 0.002 1.926 (1.116-3.323) 0.019 Stage, III & IV (vs I & II) 46/75 2.263 (1.131-4.528) 0.021 2.809 (1.485-5.312) 0.001 Tumor size, cm, > 10 (vs ≤ 10) 19/75 0.625 (0.289-1.352) 0.233 0.817 (0.436-1.532) 0.529 LN metastasis, presence (vs absence) 19/75 1.200 (0.613-2.349) 0.595 1.502 (0.831-2.714) 0.178 Ascites, presence (vs absence) 30/75 1.793 (0.977-3.291) 0.060 1.645 (0.953-2.839) 0.074 Bilaterality, bilateral (vs unilateral) 41/75 1.200 (0.647-2.224) 0.563 1.423 (0.813-2.492) 0.217 CA19-9, elevated (vs normal) 8/58 0.679 (0.206-2.236) 0.524 1.086 (0.425-2.773) 0.863 CA125, elevated (vs normal) 61/68 2.898 (0.697-12.056) 0.144 2.152 (0.668-6.931) 0.199 Histologic grade, high (vs low) 63/75 4.401 (1.061-18.260) 0.041 4.341 (1.347-13.990) 0.014 DBC1, positive (vs negative) 54/75 4.277 (1.674-10.926) 0.002 2.811 (1.363-5.794) 0.005 BRCA1, positive (vs negative) 36/75 1.861 (1.007-3.438) 0.047 1.792 (1.032-3.110) 0.038 High-grade serous carcinomas (n = 63) Age, y, ≥ 60 (vs < 60) 27/63 2.090 (1.119-3.900) 0.021 1.591 (0.907-2.791) 0.105 Stage, III & IV (vs I & II) 38/63 2.188 (1.080-4.434) 0.030 2.811 (1.464-5.399) 0.002 Tumor size, cm, > 10 (vs ≤ 10) 15/63 0.736 (0.339-1.599) 0.439 0.860 (0.448-1.651) 0.650 LN metastasis, presence (vs absence) 15/63 1.520 (0.766-3.017) 0.232 1.841 (0.992-3.417) 0.053 Ascites, presence (vs absence) 26/63 1.395 (0.749-2.598) 0.294 1.340 (0.764-2.351) 0.308 Bilaterality, bilateral (vs unilateral) 36/63 1.300 (0.683-2.475) 0.424 1.452 (0.809–2.603) 0.211 CA19-9, elevated (vs normal) 6/49 0.726 (0.220-2.403) 0.600 1.344 (0.521-3.467) 0.541 CA125, elevated (vs normal) 53/58 2.220 (0.531-9.276) 0.275 1.443 (0.446-4.672) 0.540 DBC1, positive (vs negative) 50/63 4.031 (1.427-11.382) 0.008 2.540 (1.135-5.684) 0.023 BRCA1, positive (vs negative) 32/63 2.010 (1.063-3.803) 0.032 1.719 (0.973-3.038) 0.062 0.003) were associated with shorter OS and RFS (Table 2) chemotherapy, DBC1 expression was significantly associ- (Figure 2). The patients with tumors expressing DBC1 ated with shorter OS (P = 0.004, hazard ration [HR]; 3.625, had a 3.474-fold (P< 0.001, 95% confidence interval [95% 95% CI; 1.518-8.656) and RFS (P = 0.004, HR; 2.738, 95% CI]; 1.684-7.166) greater risk of death and a 3.007-fold CI; 1.368-5.477). BRCA1 expression predicted shorter OS (P< 0.001, 95% CI; 1.624-5.567) greater risk of relapse (P = 0.005, HR; 2.263, 95% CI; 1.287-3.979) and RFS or death. The five- and ten-year OS rates of the DBC1- (P = 0.002, HR; 2.254, 95% CI; 1.359-3.739) (Table 2). negative group were 78% and 73%, respectively, and were When we did additional analysis in the subpopulation only 42% and 36% in DBC1-positive group, respectively. of serous carcinomas, the factors significantly associated In addition, among the 83 patients who received adjuvant with both OS and RFS by univariate analysis were the Cho et al. Journal of Ovarian Research (2015) 8:2 Page 6 of 11 Figure 2 Kaplan-Meier survival analyses in 104 overall ovarian carcinomas. Overall survival and relapse-free survival according to the tumor stage (A), histologic grade (B), DBC1 expression (C), and BRCA1 expression (D). Figure 3 Kaplan-Meier survival analyses in 75 ovarian serous carcinomas. Overall survival and relapse-free survival according to the tumor stage (A), histologic grade (B), DBC1 expression (C), and BRCA1 expression (D). Cho et al. Journal of Ovarian Research (2015) 8:2 Page 7 of 11 age of patients (OS; P = 0.002, RFS; P = 0.019), tumor and BRCA1 expression were significantly associated with stage (OS; P = 0.021, RFS; P = 0.001), histologic grade OS (Table 2) (Figure 4). The expression of DBC1 pre- (OS; P =0.041, RFS; P = 0.014), and DBC1 expression dicted a 4.031-fold (P= 0.008, 95% CI; 1.427-11.382) (Log-rank, OS; P <0.001, RFS; P = 0.003), and BRCA1 ex- greater risk of death and a 2.540-fold (P= 0.005, 95% CI; pression (Log-rank, OS; P =0.043, RFS; P =0.034) (Table 2) 1.135-5.684) greater risk of relapse or death of high- (Figure 3). The patients who had DBC1-expressing serous grade serous carcinoma patients (Table 2). The OS rates carcinoma had a 4.277-fold (P= 0.002, 95% CI; 1.674- at five- and ten-years of DBC1-negative high-grade ser- 10.926) greater risk of death and its expression was signifi- ous carcinomas were 85% and 64%, respectively, and cantly associated with shorter RFS (P= 0.005, HR; 2.811, were 36% and 25% in DBC1-positive high-grade serous 95% CI; 1.363-5.794) (Figure 3C). carcinomas. Among the 63 high-grade serous carcinomas, tumor In the 20 cases of mucinous carcinomas, tumor stage stage and the expression of DBC1 were significantly as- was significantly associated with shorter OS (Log-rank, P< sociated with both OS and RFS, and the age of patients 0.001) and RFS (Log-rank, P< 0.001). DBC1 expression Figure 4 Kaplan-Meier survival analyses in 63 high-grade serous carcinomas. Overall survival and relapse-free survival according to the tumor stage (A), DBC1 expression (B), and BRCA1 expression (C). Cho et al. Journal of Ovarian Research (2015) 8:2 Page 8 of 11 showed borderline significancefor thepredictionofOSof and histologic grade (P= 0.009) (Table 3). In addition, the mucinous carcinoma patients (Log-rank, P= 0.060). age of the patients (P = 0.035) and the expression of DBC1 (P = 0.011) were the independent predictor of OS in Expression of DBC1 is an independent prognostic high-grade serous carcinomas. The expression of DBC1 indicator of worse survival outcome in ovarian predicted a 3.828-fold (95% CI, 1.353-10.827) greater risk carcinomas by multivariate analysis of death of high-grade serous carcinoma patients (Table 3). The factors significantly associated with OS or RFS by univariate analysis were included in the multivariate ana- Discussion lysis. Because of data for CA125 was missing in 11 patients, This study has shown that immunohistochemical ex- the CA125 level was not included in the multivariate ana- pression of DBC1 was significantly associated with ad- lysis. The factors included in the multivariate analysis of vanced clinicopathological factors of ovarian carcinoma OS and RFS were age, tumor stage, lymph node metasta- such as higher tumor stage, latent distant metastasis, sis, presence of ascites, bilaterality of the tumor, histologic platinum-resistance, elevated serum level of CA125, and grade, BRCA1 expression, and DBC1 expression. In 104 higher histologic grade. Moreover, DBC1 expression was ovarian carcinomas, the factors significantly associated significantly associated with shorter survival of ovarian with OS by multivariate analysis were age (P =0.010), carcinomas, especially in high-grade serous carcinomas. In tumor stage (P = 0.006), and DBC1 expression (P =0.021). agreement with our results, increased expression of DBC1 The patients with tumors expressing DBC1 had a 2.423 has been reported as an indicator of poor prognosis of fold (95% CI, 1.144-5.132) greater risk of death (Table 3). gastric carcinoma [15], breast carcinoma [14], colorectal Tumor stage (P< 0.001) and histologic grade (P= 0.007) carcinoma [9], esophageal carcinoma [20], clear cell renal were the independent predictor of RFS. In addition, DBC1 cell carcinoma [12], diffuse large B cell lymphoma [13], expression was an independent predictor of OS (P =0.026, and soft tissue sarcomas [13]. Nevertheless, there has been HR; 2.735, 95% CI; 1.128-6.634) among the 83 patients no report investigating DBC1 expression in ovarian car- who received adjuvant chemotherapy, as indicated by cinomas. Therefore, this is the first report that examined multivariate analysis. DBC1 expression in human ovarian tumors and suggests In the subpopulation of 75 serous carcinomas, the age of that DBC1 expression might be usable as a prognostic in- the patients (P = 0.010) and DBC1 expression (P =0.006) dicator for ovarian carcinoma patients. were the independent predictors of OS. The expression of DBC1 is interesting because of its putative role for the DBC1 predicted a 3.757-fold (95% CI, 1.462-9.653) greater inhibition of SIRT1 and has been suggested as tumor sup- risk of death. The factors significantly associated with pressor [4,16,32]. However, there have been conflicting re- RFS in serous carcinoma were tumor stage (P< 0.001) ports regarding the role of DBC1 and SIRT1 in human Table 3 Multivariate Cox regression analyses for overall survival and relapse-free survival in ovarian carcinomas Characteristics OS RFS HR (95% CI) P HR (95% CI) P Overall ovarian carcinomas Age, y, ≥ 60 (vs < 60) 2.100 (1.191-3.702) 0.010 Stage, III & IV (vs I & II) 2.488 (1.295-4.780) 0.006 3.426 (1.944-6.036) <0.001 Histologic grade, high (vs low) 3.023 (1.355-6.742) 0.007 DBC1, positive (vs negative) 2.423 (1.144-5.132) 0.021 Serous carcinomas Age, y, ≥ 60 (vs < 60) 2.241 (1.212-4.144) 0.010 Stage, III & IV (vs I & II) 3.023 (1.588-5.755) <0.001 Histologic grade, high (vs low) 4.818 (1.487-15.614) 0.009 DBC1, positive (vs negative) 3.757 (1.462-9.653) 0.006 High-grade serous carcinomas Age, y, ≥ 60 (vs < 60) 1.961 (1.050-3.664) 0.035 Stage, III & IV (vs I & II) 2.488 (1.280-4.836) 0.007 DBC1, positive (vs negative) 3.828 (1.353-10.827) 0.011 2.059 (0.907-4.677) 0.084 The variables included in the multivariate analysis were age, tumor stage, lymph node metastasis, presence of ascites, bilaterality of the tumor, histologic grade, BRCA1 expression, and DBC1 expression. The variables included in the multivariate analysis were age, tumor stage, histologic grade, BRCA1 expression, and DBC1 expression. The variables included in the multivariate analysis were age, tumor stage, BRCA1 expression, and DBC1 expression. Cho et al. Journal of Ovarian Research (2015) 8:2 Page 9 of 11 cancers. SIRT1-induced expression of various oncogenes The higher rate of distant metastatic relapse in DBC1- and formed a positive-feedback loop with the c-Myc onco- expressing ovarian carcinomas raises the possibility that gene to stimulate tumorigenesis [33,34]. However, SIRT1 DBC1 might be involved in the acquisition of resistance formed a negative-feedback loop with the c-Myc oncogene for the postoperative chemotherapies. Among the 83 ovar- in another report [35]. Moreover, the effects of the expres- ian carcinoma patients who received adjuvant chemother- sion of DBC1 and SIRT1 in human malignant tumors var- apy, the expression of DBC1 predicted shorter OS and ied according to cell type [6,9,34,36,37]. The expression of RFS. In addition, among the 55 high-grade serous carcin- both DBC1 and SIRT1 predicted shorter survival of gastric oma patients who received adjuvant chemotherapy, DBC1 carcinoma [15], breast carcinoma [14], clear cell renal cell expression was significantly associated with poor OS (P = carcinoma [12], soft-tissue sarcoma [13], and diffuse large 014, HR; 4.484, 95% CI; 1.362-14.758) and RFS (P =0.042, B cell lymphoma [13,16]. In colon cancer, DBC1 was over- HR; 2.471, 95% CI; 1.035-5.899). Moreover, DBC1 ex- expressed in colorectal cancer and predicted shorter pression correlated with platinum-resistance. All serous survival of patients [9]. In contrast, another study reported carcinoma patients having tumors with DBC1 expression that SIRT1 expression is associated with poor prognosis (100%, 16/16) showed platinum-resistance. In contrast, but DBC1 expression is associated with favorable progno- 62% (32/48) of DBC1-negative serous carcinoma patients sis of gastric cancer patients [36]. Although the expression showed platinum-resistance. Similarly, DBC1 expression of SIRT1 was higher in ovarian carcinomas compared was associated with frequent relapse and shorter survival with benign and borderline ovarian tumors, SIRT1 ex- of breast carcinoma patients who received adjuvant chemo- pression was associated favorable prognosis of ovarian therapy [14]. Although it did not reach statistical sig- carcinoma patients [38]. Therefore, poor prognosis of nificance, lower expression of DBC1 would indicate a DBC1-expressing ovarian carcinoma might be related favorable pathological response to chemotherapy [39]. to its inhibitory role for SIRT1. However, the relationship Because DBC1 is involved in the inhibition of BRCA1 between DBC1 and SIRT1 was been frequently dissociated [22] and BRCA1/2 status is important in the develop- as shown in breast cancer [6]. Moreover, the knock-down ment and progression of ovarian carcinomas, we investi- of DBC1 inhibited proliferation of liver cancer cells [37] gated the immunohistochemical expression of BRCA1 in and suppressed invasiveness of gastric cancer cells [12]. ovarian carcinomas. Although we could evaluate the im- Therefore, it may be likely that DBC1 has its own role munohistochemical expression of BRCA1, a recent report in tumorigenesis. DBC1 regulates BRCA1-mediated has shown that there is a strong correlation between the function by binding to the BRCT domain in addition to immunohistochemical expression and molecular events in the suppression of SIRT1 expression [22]. In addition, BRCA1 [30]. In this study, BRCA1 expression was signifi- DBC1 inhibits senescence of premalignant cells by dis- cantly associated with latent distant metastasis, platinum- rupting the SUV39H1-SIRT1 complex. However, DBC1 resistance, and higher histologic grade. In addition, in showed a co-inhibitory effect for SUV39H1 and SIRT1 agreement with previous reports [24,40,41], we have dem- [8]. Therefore, there is a possibility that DBC1 may have onstrated that low-expression of BRCA1 is associated with both tumorigenic and anti-tumorigenic roles [8,22]. Thus, poor survival of ovarian carcinomas. The reason why the further study is needed to explore the exact role of DBC1 patients with defective BRCA1/2 have a longer survival in tumorigenesis. times compared with BRCA1/2 wild-type carcinomas is Because the expression of DBC1 was positively corre- related with BRCA1/2-defects in cells making them more lated with higher tumor stage, higher tumor grade, and sensitive to conventional chemotherapy, especially to latent metastasis of ovarian carcinoma, there is a possi- the platinum-based chemotherapy [23,24,42]. Our re- bility that DBC1 might be involved in the acquisition of sults have also shown that BRCA1-positivity is significantly invasive and metastatic potential. Recently, it has been associated with increased platinum-resistance (Table 1). Thereby, several therapeutic applications according to the shown that DBC1 is associated with the invasive potential of esophageal squamous cell carcinoma [20] and is im- BRCA1/2 status are under evaluation. Recently, PARP in- portant in the EMT of gastric carcinoma cells [12]. Espe- hibitors have been reported as being specifically applicable to the treatment of BRCA1/2-defective cancers [43,44]. In cially, the oncogenic role of DBC1 was regulated by the kinase effect of CK2α.CK2α phosphorylates DBC1 and our study, the expression of DBC1 and BRCA1 showed that is important for the induction of EMT. Knockdown positive correlation and the expressions of both molecules was related with platinum-resistance and shorter survival of DBC1 inhibited invasiveness of gastric cancer cells and a point mutation at the phosphorylation site of DBC1 de- of ovarian carcinoma patients. Based on the inhibitory role creased the expression of MMP2, MMP9, snail, smad3, of DBC1 for the BRCA1 [22], the co-expressing pattern of and N-cadherin [12]. In addition, DBC1 induced anoikis these two molecules in the poor prognostic group of resistance that is important in tumor metastasis by activat- ovarian carcinomas is questionable and paradoxical as ing the NFkB signaling pathway in breast cancer [17]. BRCA1/2 defective cancers are more susceptible to therapy Cho et al. Journal of Ovarian Research (2015) 8:2 Page 10 of 11 [23,24,42]. This phenomenon might be related with the diverse carcinomas and its expression is predictive of prognosis roles of DBC1 in tumorigenesis and further study is needed. of ovarian carcinoma patients, especially in high-grade Another possible oncogenic role of DBC1 might be re- serous carcinomas and possibly in mucinous carcinomas. lated with its role in the co-activation of nuclear recep- In addition, DBC1 expression was significantly associated tors [18,19,21]. DBC1 co-activates estrogen receptor and with BRCA1 expression and their expressions were related androgen receptor (AR), which can be ligand-dependent with resistance to platinum-based chemotherapy and poor or ligand-independent [18,19,21]. Although there was no prognosis of ovarian carcinoma patients. Therefore, these significant correlation between the expression of DBC1 results indicate that the expression of DBC1 and BRCA1 and estrogen receptor in breast carcinoma [14], signifi- might be used for the prediction of prognosis of ovarian cant positive correlations between the expression of carcinomas. Especially, DBC1 expression might be helpful DBC1 and AR have been reported in clear cell renal cell for the prediction of the prognosis of high-grade serous carcinoma [12] and diffuse large B cell lymphoma [11]. carcinomas. In addition, these findings suggest that DBC1 Especially, the expression of both DBC1 and AR pre- and BRCA1could be potential therapeutic targets for the dicted shorter survival of cancer patients [11,12,14-16]. treatment of ovarian carcinomas according to the expres- Additionally, ovarian epithelium expressing AR and an- sion status of DBC1 and BRCA1. However, because of the drogen induced proliferation of ovarian epithelial cells limited number of non-serous cases of ovarian carcinoma and inhibited cell death [45]. In ovarian high-grade ser- subtypes in this study, further study with more cases is ous carcinomas, immunohistochemical expression of AR needed to clarify the roles of DBC1 and BRCA1 in various correlated with the S-phase fraction and AR expression histologic subtypes of ovarian carcinomas. decreased with platinum-based chemotherapy [46]. These Abbreviations reports suggest that AR is involved in the ovarian carcino- AR: Androgen receptor; CCAR2: Cell cycle and apoptosis regulator 2; genesis. Therefore, there is a possibility that DBC1 is in- CI: Confidence interval; DBC1: Deleted in breast cancer 1; EMT: Epithelial- mesenchymal transition; HR: Hazard ration; LN: Lymph node; OS: Overall volved in ovarian tumorigenesis with the interaction with survival; RFS: Relapse-free survival; TMA: Tissue microarray. AR and further study is needed. Ovarian carcinomas are a heterogeneous group of can- Competing interests The authors declare that they have no competing interests. cers that have origins and pathogenic profiles that differ according to histologic types. Therefore, when we con- Authors’ contributions sider the prognostic impact of DBC1 expression according DHJ, HSP, SHP, KMK, MJC, WSM, MJK, and KYJ participated in the study to histologic types of ovarian carcinoma, DBC1 predicted design. DHJ and SHP did the immunohistochemical staining. DHJ, SHP, KMK, MJC, WSM, MJK, and KYJ were involved in data collection and data interpretation. DHJ, shorter survival in serous carcinomas, especially in high- HSP, KMK, and KYJ participated in the statistical analysis. DHJ, HSP, SHP, KMK, grade serous carcinomas. The 10-years OS rate was only MJC, WSM, MJK, and KYJ wrote the manuscript. All authors read and approved 25% in DBC1-positive cases, and was 64% in DBC1- the final manuscript. negative cases. In mucinous carcinomas, DBC1 expression Acknowledgements was very low compared with other subtypes of ovarian This paper was supported by Research Funds of Chonbuk National University carcinomas (15% in mucinous carcinoma, 72% in serous in and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2008-0062279). We thank DB Leveson-Gower carcinoma, and 100% in endometrioid carcinoma). How- who provided medical writing services. ever, despite the low frequency of DBC1-positivity and the small number of cases of mucinous carcinoma, DBC1 Author details Department of Obstetrics and Gynecology, Chonbuk National University expression showed borderline significance in OS analysis Medical School and Research Institute of Clinical Medicine, Jeonju, Republic (Log-rank, P = 0.060). The 10-years OS rates of DBC1- of Korea. Departments of Pathology, Chonbuk National University Medical negative and DBC1-positive mucinous carcinomas were School, Research Institute of Clinical Medicine and Research Institute for Endocrine Sciences, Jeonju, Republic of Korea. Division of Gynecologic 76% and 33%, respectively. In line with our results, DBC1 Oncology, Department of Obstetrics and Gynecology, Stanford University expression was associated with a higher nuclear grade of School of Medicine, Stanford, California, USA. breast carcinoma [39]. 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Published: Feb 15, 2015

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