Breast Cancer Susceptibility Gene 1 Expression Research Articles

Predictive value of BRCA1 expression on the efficacy of chemotherapy based on anti-microtubule agents: a pooled analysis across different malignancies and agents.

Breast cancer susceptibility gene 1 (BRCA1) expression has been suggested as a predictor in anti-neoplastic treatment with anti-microtubule agents. However, the existing evidence is conflicting. Consulting the literature, we sought to examine the true impact of BRCA1 expression on the efficacy of anti-microtubule agents. Medline by PubMed and Embase databases were searched for eligible studies. The primary endpoints were objective response rate (ORR) and progression free survival (PFS). Additional subgroup analyses stratified for detection methods, regimen, and patient origin were also performed. A total of 13 relevant studies involving a total of 1,490 cases were enrolled. Involved agents included paclitaxel, docetaxel and vinorelbine; Malignancies included non-small cell lung cancer, gastric cancer, esophageal carcinoma, ovarian carcinoma, malignant pleural mesothelioma, breast cancer, and small cell lung cancer. Through meta-analyses, we observed a potentially greater ORR in the population with high BRCA1 expression vs. low BRCA1 expression (OR 1.63, 95% CI: 0.92 to 2.88, P=0.09) but the heterogeneity is severe (P=0.01; I(2)=61%). Similar results were observed in PFS (high vs. low expression, HR 0.93, 95% CI: 0.75 to 1.15, P=0.49; heterogeneity, P<0.01, I(2)=75%). After stratification by testing methods, a significantly higher ORR in the population with high BRCA1 expression was shown in the subgroup using mRNA as a quantitative method (OR 2.90, 95% CI: 1.92 to 4.39, P<0.01; I(2)=0) whereas the difference in the subgroup using immunohistochemistry (IHC) was not significant (OR 0.60, 95% CI: 0.33 to 1.10, P=0.10; I(2)=0). Stratification by regimen (platinum-based vs. non platinum-based) and patient origin (Asian vs. Caucasian) did not reduce the heterogeneity. Although the predictive value of BRCA1 expression on the anti-microtubule chemotherapy remained uncertain based on overall results, our exploratory analyses suggested that detection using mRNA might be a preferred technique, however, further validation is required to substantiate our findings.

Nuclear PARP1 expression and its prognostic significance in breast cancer patients.

Poly(adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP1) plays important roles in DNA damage response pathways and is often overexpressed in various human tumors. Currently, the use of PARP inhibitors for breast cancer (BC) therapy is the subject of debate, and there is an urgent need to understand much the expression and prognostic role of the PARP1 protein. The aim was to investigate the clinicopathological and prognostic significance of PARP1 in BC patients. The PARP1 and breast cancer susceptibility gene 1 (BRCA1) protein expressions were evaluated in 114 BCs by immunohistochemistry. Disease-free survival (DFS) and overall survival (OS) were determined based on the Kaplan-Meier method. Our results showed that nuclear PARP1 expression was significantly associated with peritumoral vascular invasion (P = 0.046), chemotherapeutic treatment (P = 0.026), oestrogen receptor (ER; P = 0.013), human epidermal growth factor receptor 2 (HER2; P = 0.003) and BRCA1 (P < 0.001) expression. Survival analyses showed a significant association with clinical outcome in the subgroup of ER-negative patients (P = 0.017 for DFS and P = 0.048 for OS) and in the subgroup of patients treated with chemotherapeutic agents (P = 0.042 for DFS and P = 0.046 for OS). A significant correlation was also found for DFS in patients characterized by tumors without peritumoral vascular invasion (P = 0.022). More importantly, multivariate analyses revealed that high nuclear PARP1 expression was associated with decreased DFS (P = 0.012) and OS (P = 0.026). In conclusion, PARP1 expression may be used as an independent prognostic factor in BC patients. In addition, this study demonstrated that high PARP1 expression may represent a marker of poorer prognosis both for patients with worse clinical outcome and in less aggressive clinical conditions.

Correlation between BRCA1 and TopBP1 protein expression and clinical outcome of non-small cell lung cancer treated with platinum-based chemotherapy.

To investigate the correlation between protein expression of breast cancer susceptibility gene 1 (BRCA1) and topoisomerase IIβ-binding protein 1 (TopBP1) and clinical outcome of non-small cell lung cancer treated with platinum-based chemotherapy. Immunohistochemical staining was conducted to detect the protein expression of BRCA1 and TopBP1 in 101 cases of NSCLC and to correlate these with clinical features, disease progression, and patient survival. Chi-square test (χ (2)-test) was used to evaluate categorical variables. Spearman's rank order correlation was used to analyze continuous variables. Overall survival rate of NSCLC patients was analyzed by Kaplan-Meier survival curve and log-rank test. Relevant factors affecting the survival of patients with advanced NSCLC were analyzed by COX proportional hazards regression model. A total of 101 NSCLC patients were included in the present study. In tumor tissue specimens, positive expression rates of BRCA1 and TopBP1 proteins were 51.5 and 57.4%, respectively. A significant correlation between the positive expression of BRCA1 and the positive expression of TopBP1 was observed (P<0.001, r=0.326). No significant correlation between BRCA1/TopBP1 and age, gender, smoking status, performance status score, pathohistological type, or clinical stage was detected (P>0.05). During the follow-up period, 65 patients died, and 86 patients showed progression at the end of the study. The survival rate of patients with negative BRCA1 protein expression was higher than that in patients with positive BRCA1 protein expression [median overall survival (OS) 34 vs. 21months, HR 1.913, 95% CI 1.161-3.150, P=0.011]. Similarly, the survival rate of patients with negative TopBP1 expression was higher than that in patients with positive TopBP1 (median OS 36 vs. 23months, HR 1.931, 95% CI 1.157-3.224, P=0.012). No significant correlation between protein expression of BRCA1 or TopBP1 with NSCLC disease progression was observed (P>0.05). The present study indicates NSCLC patients with negative BRCA1 and TopBP1 expression showed better prognosis than those with positive protein expression.

Predictive value of BRCA1 expression on the efficacy of chemotherapy based on anti-microtube agents: a pooled analysis across different malignancies and agents.

e22246 Background: Breast cancer susceptibility gene 1 (BRCA1) expression has been suggested as a predictor in the cancer treatment with anti-microtube agents. However, existed evidence did not com...

BRCA1 germline mutation and glioblastoma development: report of cases

BackgroundGermline mutations in breast cancer susceptibility gene 1 (BRCA1) increase the risk of breast and ovarian cancers. However, no association between BRCA1 germline mutation and glioblastoma malignancy has ever been highlighted.Here we report two cases of BRCA1 mutated patients who developed a glioblastoma multiform (GBM).Cases presentationTwo patients diagnosed with triple negative breast cancer (TNBC) were screened for BRCA1 germline mutation. They both carried a pathogenic mutation introducing a premature STOP codon in the exon 11 of the BRCA1 gene. Few years later, both patients developed a glioblastoma and a second breast cancer. In an attempt to clarify the role played by a mutated BRCA1 allele in the GBM development, we investigated the BRCA1 mRNA and protein expression in breast and glioblastoma tumours for both patients. The promoter methylation status of this gene was also tested by methylation specific PCR as BRCA1 expression is also known to be lost by this mechanism in some sporadic breast cancers.ConclusionOur data show that BRCA1 expression is maintained in glioblastoma at the protein and the mRNA levels, suggesting that loss of heterozygosity (LOH) did not occur in these cases. The protein expression is tenfold higher in the glioblastoma of patient 1 than in her first breast carcinoma, and twice higher in patient 2. In agreement with the high protein expression level in the GBM, BRCA1 promoter methylation was not observed in these tumours.In these two cases, despite of a BRCA1 pathogenic germline mutation, the tumour-suppressor protein expression is maintained in GBM, suggesting that the BRCA1 mutation is not instrumental for the GBM development.

Clinicopathological Significance of BRCA1 Promoter Hypermethylation in Thai Breast Cancer Patients

Breast cancer susceptibility gene 1 (BRCA1), mapped on chromosome 17q21, is implicated in the mechanisms of cellular DNA repair. Inactivation of this gene is involved in the development of many human cancers, including breast cancer. This study aimed to investigate the prognostic value of BRCA1 promoter hypermethylation and expression in breast cancer cases. Sixty-one breast cancers were examined for BRCA1 hypermethylation by methylation-specific polymerase chain reaction (PCR), and 45 paired normal breast tissues were analyzed for altered BRCA1 mRNA levels by quantitative real-time reverse transcription-polymerase chain reaction (qRT- PCR). Aberrant methylation status in BRCA1 was detected in 15 of 61 cases (24.6%), while reduced expression was found in 7 of 45 (15.6%). BRCA1 hypermethylation was statistically associated with tumor grade III (p=0.04), a high frequency of stage IIB (p=0.02), and triple-negative phenotype (OR= 3.64, 95%CI =1.1-12.3, p=0.03). Our findings indicated that BRCA1 promoter hypermethylation is a useful prognostic marker for breast cancer.

Prognostic significance of BRCA1, ERCC1, RRM1, and RRM2 in patients with advanced non-small cell lung cancer receiving chemotherapy.

The aim of this study was to examine the prognostic value of breast cancer susceptibility gene 1 (BRCA1), excision repair cross-complementation 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), and ribonucleotide reductase subunit M2 (RRM2) in patients with advanced non-small cell lung cancer (NSCLC) who received platinum-based chemotherapy. A total of 214 patients with histologically or cytologically confirmed advanced NSCLC were enrolled in this study. The relative complementary DNA (cDNA) quantification for BRCA1, ERCC1, RRM1, and RRM2 was conducted using a fluorescence-based, real-time detection method, and β-actin was used as a reference gene. A strong correlation was observed between ERCC1 and RRM1 messenger RNA (mRNA) levels (P = 0.0385). There were inverse significant correlations between BRCA1 and ERCC1 (P < 0.0001) or RRM1 (P < 0.0001) mRNA levels. As BRCA1 levels increased, the probability of response increased (odds ratio [OR] = 0.49; P < 0.001) and the risk of progression (hazard ratio [HR] = 1.52; P = 0.034) and death (HR = 1.45; P = 0.024) decreased. As ERCC1, RRM1, and RRM2 levels increased, the probability of response decreased (ERCC1, OR = 0.42, P < 0.001; RRM1, OR = 0.85, P = 0.083; RRM2, OR = 0.42, P = 0.005) and the risk of progression (ERCC1, HR = 1.59, P = 0.002; RRM1, HR = 1.48, P = 0.039; RRM2, HR = 1.49, P = 0.041) and death (ERCC1, HR = 1.62, P = 0.008; RRM1, HR = 1.52, P = 0.023; RRM2, HR = 1.48, P = 0.017) increased. At multivariate analysis, low expression of ERCC1 was shown to be an independent predictive factor for response to chemotherapy (P = 0.018), time to progression (P = 0.025), and overall survival (P = 0.038). Furthermore, concomitant low expression levels of ERCC1, RRM1, and RRM2 and the high expression level of BRCA1 were predictive of a better outcome (P = 0.014). This study suggests that the efficacy of platinum-based chemotherapy can be improved when customized according to the mRNA expression of BRCA1, ERCC1, RRM1, and RRM2.

BRCA1 promoter hypermethylation in sporadic epithelial ovarian carcinoma: Association with low expression of BRCA1, improved survival and co-expression of DNA methyltransferases.

The breast cancer susceptibility gene 1 (BRCA1) inactivation in sporadic epithelial ovarian carcinoma (EOC) is common and low BRCA1 expression is associated with promoter hypermethylation. The clinical validation of BRCA1 methylation as a prognostic marker in EOC remains unresolved. The aim of the present study was to determine the aberrant promoter methylation of BRCA1 in benign and malignant ovarian tumor tissues, to establish the association with the clinicopathological significance and the prognostic value. Additionally, the contribution of DNA methyltransferase (DNMT) expression to BRCA1 promoter hypermethylation was determined. The rate of BRCA1 methylation was observed to be 35.2% (50/142) in the EOCs; however, no methylation (0/32) was observed in the benign tumors. BRCA1 methylation was significantly associated with the downregulation of BRCA1 expression (P<0.001) and the frequency of BRCA1 methylation was greater in the carcinomas of patients whose tumor was bilateral than that of patients with a unilateral carcinoma (P=0.015). BRCA1 methylation was significantly associated with the preoperative serum carbohydrate antigen-125 level (P=0.013), improved overall survival (P=0.005) and disease-free survival (P=0.007). In addition, a significant correlation was observed between the co-expression of DNMTs and the methylation status of BRCA1. Thus, the present study provided support for BRCA1 promoter hypermethylation as a prognostic marker for survival in sporadic EOC, and co-expression of DNMTs was observed to contribute to BRCA1 promoter hypermethylation.

Cinnamaldehyde/chemotherapeutic agents interaction and drug-metabolizing genes in colorectal cancer

Cinnamaldehyde is an active monomer isolated from the stem bark of Cinnamomum cassia, a traditional oriental medicinal herb, which is known to possess marked antitumor effects in vitro and in vivo. The aim of the present study was to examine the potential advantages of using cinnamaldehyde in combination with chemotherapeutic agents commonly used in colorectal carcinoma (CRC) therapy, as well as to investigate the effect of cinnamaldehyde on chemotherapeutic-associated gene expression. The synergistic interaction of cinnamaldehyde and chemotherapeutic agents on human CRC HT-29 and LoVo cells was evaluated using the combination index (CI) method. The double staining with Annexin V conjugated to fluorescein-isothiocyanate and phosphatidylserine was employed for apoptosis detection. The expression of drug-metabolizing genes, including excision repair cross‑complementing 1 (ERCC1), orotate phosphoribosyltransferase (OPRT), thymidylate synthase (TS), breast cancer susceptibility gene 1 (BRCA1) and topoisomerase 1 (TOPO1), all in HT-29 and LoVo cells, with or without the addition of cinnamaldehyde, was examined by quantitative polymerase chain reaction (PCR). Cinnamaldehyde had a synergistic effect on the chemotherapeutic agents cytotoxicity in HT-29 and LoVo cells. In addition, cinnamaldehyde suppressed BRCA1, TOPO1, ERCC1 and TS mRNA expression, except for OPRT expression, which was markedly upregulated. Our findings indicate that cinnamaldehyde appears to be a promising candidate as an adjuvant in combination therapy with 5-fluorouracil (5-FU) and oxaliplatin (OXA), two chemotherapeutic agents used in CRC treatment. The possible mechanisms of its action may involve the regulation of drug‑metabolizing genes.

Pattern of Breast Cancer Susceptibility Gene 1 Expression Is a Potential Prognostic Biomarker in Resectable Pancreatic Ductal Adenocarcinoma

The tumor-suppressor breast cancer susceptibility gene 1 (BRCA1) is a nuclear-cytoplasmic shuttling protein that when in the nucleus is required for DNA repair whereas when in the cytoplasm is important in activating cell death processes. Although BRCA1 mutations have been shown to be associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC), its role in disease progression is yet to be determined. We hypothesized that BRCA1 expression pattern could be used as a prognostic biomarker. Sixty-seven patients who underwent resections for PDAC were included. A tissue microarray was constructed, stained with antibodies to BRCA1, and scored for intensity and subcellular location. Univariate and multivariate statistical analyses were performed. An increase in cytosolic BRCA1 distribution was associated with higher pathologic stage (P = 0.006). Nuclear-cytosolic BRCA1 distribution was associated with a decrease in recurrence-free survival with a hazards ratio of 1.4 (P = 0.059). Decreased BRCA1 intensity was associated with higher pathologic stage (P = 0.027), but BRCA1 intensity was not associated with overall survival or recurrence-free survival. Our results demonstrate a possible association of BRCA1 expression pattern with pathologic stage, implying a potential role of BRCA1 in PDAC development and progression.

A functional BRCA1 coding sequence genetic variant contributes to risk of esophageal squamous cell carcinoma

As a tumor suppressor, breast cancer susceptibility gene 1 (BRCA1) plays a pivotal role in maintaining genomic stability. A functional rs799917 T>C polymorphism located in the BRCA1 coding sequence could influence miR-638-mediated regulation of BRCA1 expression. Therefore, we examined the association between this polymorphism and esophageal squamous cell carcinoma (ESCC) risk as well as its biological function. Genotypes were determined in two independent case-control studies consisted of 1128 ESCC patients and 1150 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. The allele-specific regulation on BRCA1 expression by the polymorphism was investigated in vitro and in vivo. We found that the BRCA1 rs799917 CC genotype was significantly associated with increased ESCC risk compared with the TT genotype in both studies (Jinan population: OR = 1.28, 95% CI = 1.04-1.58, P = 0.020; Huaian population: OR = 1.46, 95% CI = 1.17-1.83, P = 0.001). Stratified analyses with pooled data indicated that a multiplicative interaction between rs799917 and smoking or drinking in intensifying ESCC risk was evident (gene-smoking: P interactio n = 5.8 × 10(-5); gene-drinking: P interaction = 7.1 × 10(-7)). In vitro experiments indicate that miR-638 could negatively regulate BRCA1 expression and enhance proliferation of ESCC cells. In vivo BRCA1 messenger RNA expression analyses showed that the rs799917 C allele carriers had significantly decreased BRCA1 expression in both normal and cancerous esophagus tissues compared with T allele carriers, suggesting that lower BRCA1 expression may lead to higher risk for malignant transformation of esophagus cells. These results suggest that BRCA1 functional rs799917 polymorphism is involved in susceptibility to developing ESCC, alone and in a gene-environment interaction manner.

Abstract 3697: Molecular link that associates high fat diet and prostate tumor growth.

Abstract Prostate Cancer (PCa) is one of the most common invasive tumors in men. Epidemiological studies indicate that diet and overweight are important factors implicated in prostate carcinogenesis. Obesity is associated with PCa aggressiveness, poorer prognosis and increased mortality. Breast cancer susceptibility gene 1 (BRCA1) interacts with several transcriptional regulators to modulate the androgen receptor (AR) signaling in PCa cell lines. Germline mutations in this gene increase breast cancer risk and are associated with high grade PCa. Previously, it had been reported that C-terminal Binding Protein 1 (CtBP1) acts as a switch to control BRCA1 transcription in response to the metabolic status of the cells. The release of CtBP1 from BRCA1 promoter through estrogen induction and high NAD+/NADH ratio (similar to high caloric intake) increases BRCA1 transcription in breast cancer cells. The aim of this work was to assess the effect of androgens and/or high fat diet over the BRCA1/CtBP1 axis and PCa tumor growth. We found that BRCA1 and CtBP1 proteins associate to BRCA1 proximal promoter region in PC3 cells and suppress BRCA1 transcription. Testosterone stimulation released these factors from BRCA1 promoter increasing its transcription. To assess whether this activation is mediated by testosterone or the estrogen, synthesized from testosterone by the aromatase (CYP19A1), we investigated this mechanism in the presence of letrozol (LTZ), an aromatase inhibitor. We found that LTZ abolished BRCA1 induction by testosterone, suggesting that BRCA1 activation is mediated by estrogen in these cells. Furthermore, we generated PC3 cell lines transfected with pcDNA3-CtBP1 (PC3-CtBP1) or shRNA-CtBP1 (PC3-shCtBP1) plasmids, to overexpress or knock down CtBP1 expression, respectively. CtBP1 induction decreased BRCA1 expression in these cells and this effect was reverted by CtBP1 depletion. In addition, PC3-CtBP1 cells showed increased clonogenic capacity and proliferation compared to PC3-shCtBP1 cells. Moreover, we developed an in vivo model to investigate the effect of high caloric diet on PCa growth after CtBP1 modulated-expression. High fat or control diet fed male nude mice were inoculated with PC3-CtBP1 and PC3-shCtBP1 stable cells. We found that CtBP1 depleted cells growing as xenografts in high fat diet fed mice dramatically decreased prostate tumor growth. Molecular analysis of tumors by RT-qPCR showed that CtBP1 depletion correlated with high BRCA1 expression. In addition, serum from high fat fed mice significantly induced PC3-CtBP1 cell proliferation in vitro. These results strongly suggest that the potential oncogenic role of CtBP1 is dependent on the caloric diet intake. Hence, BRCA1 regulation by CtBP1 provides an important molecular link between caloric intake and tumor suppressor expression. Citation Format: Cristian P. Moiola, Paola De Luca, Florencia Zalazar, Javier Cotignola, Estefania Labanca, Roberto Meiss, Elba S. Vazquez, Kevin Gardner, Adriana De Siervi. Molecular link that associates high fat diet and prostate tumor growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3697. doi:10.1158/1538-7445.AM2013-3697

Breast cancer susceptibility gene 1 (BRCA1) predict clinical outcome in platinum- and toxal-based chemotherapy in non-small-cell lung cancer (NSCLC) patients: a system review and meta-analysis

The recent studies have evaluated the relationship between BRCA1 expression and clinical outcome of chemotherapy (mainly focused on platinum-based and toxal-based treatment) in NSCLC patients, but the results were inconclusive and controversial. Our aim of this study was to evaluate this association by literature based system review and meta-analysis.PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) databases were used to retrieve the relevant articles. The interested outcome included objective response rate (ORR), overall survival (OS) and event-free survival (EFS). The pooled odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) ware estimated.After specific inclusion and exclusion criteria, 23 studies fulfilled the criteria and were included in our analysis. In 17 platinum-based studies, low/negative BRCA1 was in favor of better ORR (OR = 1.70, 95%CI = 1.32-2.18), longer OS and EFS (HR = 1.58, 95%CI = 1.27-1.97, and HR = 1.60, 95%CI = 1.07-2.39 for OS and EFS, respectively). In 4 toxal-based chemotherapy studies, the patients with high/positive BRCA1 had better ORR (OR = 0.41, 95%CI = 0.26-0.64), OS and EFS were not evaluated as the insufficient data available.Overall, BRCA1 might be a useful biomarker to predict clinical outcome for personal chemotherapy in NSCLC patients in the future.

BRCA1 and ERCC1mRNA levels are associated with lymph node metastasis in Chinese patients with colorectal cancer

BackgroundAlthough both excision repair cross-complementing group 1 (ERCC1) and breast cancer susceptibility gene 1 (BRCA1) can be effective biomarkers for chemosensitivity in primary malignant tumors, their applicability to metastases is poorly understood. Here, ERCC1 and BRCA1, which are linked to lymph node metastasis (LNM) in colorectal cancer (CRC), were evaluated in primary CRC samples from Chinese patients with LNM (LNM CRC) or without LNM (non-LNM CRC). mRNA levels of ERCC1 and BRCA1 in CRC samples, and their relationships to primary CRC and LNM, were also examined.MethodsDifferences in BRCA1 and ERCC1 gene expression between primary CRC with or without LNM were assessed in CRC samples from 120 Chinese patients, using real-time polymerase chain reaction. Relationships between ERCC1 and BRCA1 expression and clinicopathological parameters and prognoses were also examined.ResultsERCC1 and BRCA1 were significantly down-regulated in LNM CRC compared with non-LNM CRC. Down-expression of ERCC1 and BRCA1 was significantly associated with LNM (P < 0.001), advanced TNM stage (P < 0.001), and decreased 5-year overall survival rate (P < 0.001). Univariate and multivariate analyses showed ERCC1 and BRCA1 expression as independent predictors of recurrence and survival in CRC patients (P < 0.05).ConclusionsERCC1 and BRCA1 mRNA expression levels correlate inversely to CRC metastasis. ERCC1 and BRCA1 might serve as biomarkers for LNM and as prognostic indicators for CRC; their down-expressions are predictors of poor outcome in CRC patients.

BRCA1 mRNA Expression as a Predictive and Prognostic Marker in Advanced Esophageal Squamous Cell Carcinoma Treated with Cisplatin- or Docetaxel-Based Chemotherapy/Chemoradiotherapy

BackgroundThe molecular backgrounds that determine therapeutic effectiveness in esophageal cancer remain largely unknown. Breast cancer susceptibility gene 1 (BRCA1) expression has been found to switch the response to cisplatin- or paclitaxel-based chemotherapy. It remains unclear how variations in BRCA1 expression influence clinical outcomes in esophageal cancer.Patients and MethodsQuantitative real-time polymerase chain reaction (qPCR) was performed to examine BRCA1 mRNA expressions in paraffin-embedded specimens from 144 patients with advanced or metastatic esophageal squamous cell carcinoma who received cisplatin- or docetaxel-based first-line treatments.ResultsLow BRCA1 mRNA expression correlated with increased response rate (RR; P = 0.025 and 0.017, respectively) and median overall survival (mOS; P = 0.002 and P<0.001, respectively) in cisplatin-based chemotherapy or chemoradiotherapy group and also correlated with decreased RR (P = 0.017 and 0.024, respectively) and mOS (both P<0.001) in docetaxel-based chemotherapy or chemoradiotherapy group. Multivariate analysis revealed that low BRCA1 expression was an independent prognostic factor in cisplatin-based chemotherapy (HR 0.29; 95%CI 0.12–0.71; P = 0.007) or chemoradiotherapy (HR 0.12; 95%CI 0.04–0.37; P<0.001) group and higher risk for mortality in docetaxel-based chemotherapy (HR 5.02; 95%CI 2.05–12.28; P<0.001) or chemoradiotherapy (HR 7.02; 95%CI 2.37–27.77; P<0.001) group.ConclusionsBRCA1 mRNA expression could be used as a predictive and prognostic marker in esophageal cancer who underwent first-line cisplatin- or docetaxel-based treatments.

686P - Overall Survival (OS) to First- and Second-Line Chemotherapy Associated with Mrna Expression of Multiple Myeloma Set (MMSET) Domain, P53-Binding Protein 1 (53bp1) and Breast Cancer Susceptibility Gene 1 (BRCA1) in advanced Gastric Cancer Patients (P)

ABSTRACT Background Low BRCA1 expression enhances sensitivity to platinum, while high levels increase sensitivity to taxanes (Quinn et al. Cancer Res 2003). In response to cisplatin-induced DNA double strand breaks (DSBs), MDC1 binds to γH2AX, promoting DSB repair by 53BP1 and BRCA1. MMSET is required for the accretion of 53BP1, PIAS4 and Ubc9 to DSB sites. We hypothesized that the mRNA expression of these components of the MDC1-MMSET-53BP1 pathway could impact the predictive model based on BRCA1 mRNA expression (Wei et al. JNCI 2011). Methods Tumor samples were obtained from 132 advanced gastric cancer p treated with first-line FOLFOX, 58 of whom also received second-line docetaxel. mRNA expression of MDC1, MMSET, 53BP1, PIAS4, Ubc9 and BRCA1 was analyzed by real-time PCR. Results A close correlation was found between MMSET and BRCA1 (r = 0.28; P = 0.002), 53BP1 (r = 0.54; p Conclusions Longer OS to FOLFOX was associated with low levels of both MMSET and 53BP1, while longer OS to second-line docetaxel was associated with high levels of both MMSET and BRCA1. MMSET, together with 53BP1 or BRCA1 can be useful for customizing chemotherapy in advanced gastric cancer p. Disclosure All authors have declared no conflicts of interest.

BRCA1 and HSP90 cooperate in homologous and non-homologous DNA double-strand-break repair and G2/M checkpoint activation

Expression of functional breast cancer susceptibility gene 1 (BRCA1) in human breast and ovarian cancers is associated with resistance to platinum-based chemotherapeutics and poly(ADP ribose) polymerase (PARP) inhibitors. BRCA1 is a nuclear tumor suppressor that is critical for resolving double-strand DNA breaks (DSBs) and interstrand crosslinks (ICLs) by homologous recombination (HR). In vitro, animal and human clinical data have demonstrated that BRCA1-deficient cancers are highly sensitive to ICL-inducing chemotherapeutic agents, are amenable to synthetic lethal approaches that exploit defects in DSB/ICL repair, and may be associated with improved survival. Conversely, high or restored expression of BRCA1 in breast and ovarian cancer is associated with therapeutic resistance and poor prognosis. There has been much interest in identifying agents that interfere with BRCA1-dependent DSB/ICL repair to restore or enhance sensitivity to cancer therapeutics. We demonstrate that the heat-shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin [17-AAG (Tanespimycin)], currently in Phase II/III clinical evaluation for several cancers, induces BRCA1 ubiquitination and proteasomal degradation, resulting in compromised repair of ionizing radiation- and platinum-induced DNA damage. We show that loss of HSP90 function abolishes BRCA1-dependent DSB repair and that BRCA1-deficient cells are hypersensitive to 17-AAG due to impaired Gap 2/Mitosis (G2/M) checkpoint activation and resultant mitotic catastrophe. In summary, we document an upstream HSP90-dependent regulatory point in the Fanconi anemia/BRCA DSB/ICL repair pathway, illuminate the role of BRCA1 in regulating damage-associated checkpoint and repair responses to HSP90 inhibitors, and identify BRCA1 as a clinically relevant target for enhancing sensitivity in refractory and/or resistant malignancies.

BRCA1 Regulates Follistatin Function in Ovarian Cancer and Human Ovarian Surface Epithelial Cells

Follistatin (FST), a folliculogenesis regulating protein, is found in relatively high concentrations in female ovarian tissues. FST acts as an antagonist to Activin, which is often elevated in human ovarian carcinoma, and thus may serve as a potential target for therapeutic intervention against ovarian cancer. The breast cancer susceptibility gene 1 (BRCA1) is a known tumor suppressor gene in human breast cancer; however its role in ovarian cancer is not well understood. We performed microarray analysis on human ovarian carcinoma cell line SKOV3 that stably overexpress wild-type BRCA1 and compared with the corresponding empty vector-transfected clones. We found that stable expression of BRCA1 not only stimulates FST secretion but also simultaneously inhibits Activin expression. To determine the physiological importance of this phenomenon, we further investigated the effect of cellular BRCA1 on the FST secretion in immortalized ovarian surface epithelial (IOSE) cells derived from either normal human ovaries or ovaries of an ovarian cancer patient carrying a mutation in BRCA1 gene. Knock-down of BRCA1 in normal IOSE cells demonstrates down-regulation of FST secretion along with the simultaneous up-regulation of Activin expression. Furthermore, knock-down of FST in IOSE cell lines as well as SKOV3 cell line showed significantly reduced cell proliferation and decreased cell migration when compared with the respective controls. Thus, these findings suggest a novel function for BRCA1 as a regulator of FST expression and function in human ovarian cells.

MRNA Expression of BRCA1, PIAS1, and PIAS4 and Survival After Second-line Docetaxel in Advanced Gastric Cancer

Breast cancer susceptibility gene 1 (BRCA1) has a central role in chemotherapy-induced DNA damage response. The protein inhibitor of activated STAT (PIAS) family of proteins, PIAS1 and PIAS4, are also necessary for adequate DNA damage repair. To further understand the role of BRCA1 in DNA repair, we examined the mRNA expression of these genes in 133 advanced (stage III-IV) gastric cancer patients using quantitative reverse transcription polymerase chain reaction. All P values were two-sided. The median overall survival was 12.5 months (95% confidence interval [CI] = 9.8 to 13.4 months). Among 59 patients receiving second-line docetaxel, the median overall survival was 25.8 months (95% CI = 9.2 to 42.4 months) for patients with high BRCA1 expression, 19.1 months (95% CI = 3.4 to 34.8 months) for those with intermediate expression, and 9.5 months (95% CI = 8.7 to 10.2 months) for those with low expression (P = .0062). The risk of mortality was higher in patients with low BRCA1 levels compared with high BRCA1 levels (hazard ratio of death = 2.49, 95% CI = 1.03 to 5.97, P = .037). Survival in patients receiving second-line docetaxel-based chemotherapy showed a similar trend with PIAS1 and PIAS4 mRNA expression levels, although the associations for PIAS4 were not statistically significant.

The correlation between chemotherapeutic efficacy and breast cancer susceptibility gene 1 and class IIIβ-tubulin protein expression in non-small cell lung cancer patients

To investigate the predictive value of breast cancer susceptibility gene 1 (BRCA1) and class IIIβ-tubulin protein expression in tumor tissue for the efficacy of taxol and cisplatin combined chemotherapy (TP) in stage IIIB/IV non-small cell lung cancer (NSCLC) patients. A total of 92 stage IIIB/IV NSCLC patients were recruited with 87 patients evaluated. Bronchoscopy or lung puncture tumor biopsy samples were obtained with BRCA1 and class IIIβ-tubulin protein expression examined immunohistochemically before chemotherapy. The patients were randomly assigned to be received 4 to 6 cycles of TP chemotherapy regiments and followed up until death or lost. Response rate (RR), overall survival (OS) and time to tumor progression (TTP) were assessed. Among the 87 evaluated patients, the positive expression rates of BRCA1 and class IIIβ-tubulin were 57.5% (50/87) and 48.3% (42/87) respectively. There was no significant difference in clinical characteristics among patients with different positive expression rate. According to different expression of BRCA1 and class IIIβ-tubulin, the patients were divided into four groups: group A (low expression of both BRCA1 and class IIIβ-tubulin), group B (high expression of both BRCA1 and class IIIβ-tubulin), group C (high expression of only BRCA1) and group D (high expression of only class IIIβ-tubulin). The RR was higher in group A than other three groups (60.7%, 34.8%, 9/19 and 6/17 respectively). The OS and TTP were longer in group A than other three groups [OS: (539.4 ± 17.6) days, (267.2 ± 20.5) days, (325.6 ± 24.1) days and (283.7 ± 26.2) days respectively; TTP: (256.9 ± 28.4) days, (143.8 ± 17.6) days, (179.3 ± 19.8) days and (152.6 ± 23.5) days respectively]. There were no significant differences among the other three groups. The expression level of BRCA1 and class IIIβ-tubulin in tumor tissue is probably a predictor for the efficacy of TP chemotherapy in NSCLC patients. TP chemotherapy is more suitable for the NSCLC patients with lower expression of both BRCA1 and class IIIβ-tubulin. Our study may provide a new sight for tailored chemotherapy in NSCLC patients.