BRCA1 Expression Research Articles

THE PROGNOSTIC SIGNIFICANCE OF BRCA1 GENE EXPRESSION IN PATIENTS WITH BREAST CANCER

Nowadays, BRCA-associated breast cancer occupies a special position in the choice of treatment strategy. Although, the drug treatment of such patients was almost the same as the treatment of sporadic disease. Of particular interest is the assessment of the deficit of homologous recombination, which may include various dysfunctions of the BRCA1 gene. Moreover, it has been shown that a decrease in the functional activity of BRCA1 is reflected in the sensitivity of the tumor to DNA damaging agents, and the prognosis of the disease becomes more favorable. Aim: assessment of the association of BRCA1 gene expression in a breast tumor with the prognosis of the disease. Materials and methods. The study included 111 patients with breast cancer T1-4N0-3M0 (stage IIA - IIIB), with a morphologically verified diagnosis. Initial and postoperative expression of BRCA1 in tumor material was evaluated. RNA was isolated from the tumor material before treatment and after NAC. The level of BRCA1 expression was assessed using reverse transcriptase quantitative real-time PCR (RT-qPCR). Results. As a result of the study, long-term results of treatment of patients were evaluated depending on the level of BRCA1 gene expression. The presence of BRCA1 hypoexpression (level less than 1) in tumor tissue after NAC was found to be a favorable prognostic factor and is associated with high rates of metastasis-free survival (p=0.0002). In addition, a similar result is shown for patients treated with the FAC NAC regimen (p=0.005). An interesting result was demonstrated for 8 patients who underwent chemotherapy with the inclusion of platinum drugs. All patients had a low postoperative expression level of BRCA1 and 100% non-metastatic and overall survival. Conclusion. Thus, the data obtained indicate the prognostic significance of BRCA1 gene expression in a breast tumor after neoadjuvant chemotherapy.

MRNA expression of chemosensitivity genes as a predictor of response to neoadjuvant chemotherapy in non-small cell lung cancer

The objective response rate to neoadjuvant chemotherapy (NAC) in patients with non-small cell lung cancer (NSCLC) is approximately 16 %. Therefore, the search for new predictive factors and markers that could precisely predict the NAC response and be relevant to the choice of the adequate treatment policy is of utmost importance. the purpose of the study was to analyze the relationship between the expression levels of chemosensitivity genes and NAC response in patients with non-small cell lung cancer. material and methods. The study included 30 patients with stage IIAIIIB NSCLC. Total RNA was isolated from normal and tumor lung tissue samples prior to NAC. The expression level of chemosensitivity genes, such as BRCA1, RRM1, ERCC1, TOP1, TOP2a, TUBB3, TYMS, and GSTP1 was evaluated by real-time reverse transcriptase quantitative PCR (RT-qPCR). results. A significant difference in the expression levels of the studied genes between patients with different NAC response was found. The objective response to therapy was observed in 67 % (10/15) of patients having no ERCC1 expression compared to those with ERCC1 expression (p<0.05). Low (less than 0.2) and high (more than 1.2) BRCA1 expression levels were associated with low rates of NAC response compared with patients whose expression level was between the lower and upper quartiles. Statistically significant differences were shown for the GSTP1 and RRM1 genes. conclusion. A comprehensive assessment of the expression of chemosensitivity genes is important not only in terms of understanding heterogeneity and complexity of the molecular biology of NSCLC, but also for more accurate prediction of response to NAC and identification of potential drug targets.

Significance of BRCA1 expression in breast and ovarian cancer patients with brain metastasis – A multicentre study

PurposeCerebral metastases develop in 10–30% of patients with breast cancer (BC) and in around 3.3 to 4% of patients with ovarian cancer (OC). The aim of the multicenter study is to investigate the correlation between the expression of estrogen alpha receptors (ERα), progesterone receptors (PR), human epidermal growth factor receptor 2 (HER2), stromal cell-derived factor 1 (SDF1) and its receptor C-X-C chemokine receptor type 4 (CXCR4), breast cancer metastasis suppressor 1 (BRMS1), astrocyte elevated gene 1 (AEG1), depending on the status of BRCA1 protein, in patients suffering from OC and BC with brain metastases. Patients and methodsThe analysis included 51 patients: 29 with BC and 22 with OC, in whom brain metastases were disclosed. ResultsIn most patients (65.5% of BC patients and 68.2% of patients with OC tumors) BRCA1 protein loss was found. No correlation was disclosed between the levels of ERα, PR receptors, HER2, SDF1, CXCR4, AEG1, BRMS1 and BRCA1 status, patient age, stage of disease advancement, grade of histological maturity of the cells, presence of metastases to lymph nodes. A statistically significant correlation was disclosed between the negative expression of PR receptors and a high expression of CXCR4 in patients with BC. High values of the AEG1 protein (linked to metastases) were detected alongside a high expression of BRMS1 (a suppressor of metastases). ConclusionsPatients with BC and OC and brain metastases have a frequent loss of BRCA1 expression. The role of ERα, PR, HER2, SDF1, CXCR4, AEG1, BRMS1 in metastatic process needs further studies.

Expression and prognostic significance of Fanconi anemia group D2 protein and breast cancer type 1 susceptibility protein in familial and sporadic breast cancer.

Fanconi anemia group D2 protein (FANCD2) and breast cancer type 1 susceptibility protein (BRCA1), within the FA/BRCA pathway, are involved in the regulation of DNA damage repair, which is associated with breast cancer (BC) progression. The present study aimed to investigate BRCA1 and FANCD2 expression in breast cancer, and to highlight the association with patient clinical characteristics and prognoses. The BRCA1 and FANCD2 proteins were detected by immunohistochemistry in 335 tissue samples obtained from patients with BC, including 141 patients with familial BC (FBC), 147 patients with sporadic breast cancer (SBC) and 47 patients with benign breast tumors. Western blotting was used to detect the FANCD2 ubiquitination level in 56 frozen specimens that were randomly selected from the SBC group. Protein expression of BRCA1 in the FBC group was positively associated with tumor size, lymphatic invasion, Tumor-Node-Metastasis (TNM) stage, estrogen receptor (ER) status and FANCD2 expression. Protein expression of FANCD2 in the SBC group was positively associated with tumor size, TNM stage, ER status and Ki-67 index. Survival analyses revealed that BRCA1 expression was associated with the decreased disease-free survival (DFS) rate of patients with FBC (versus no BRCA1 expression) and that FANCD2 was associated with decreased DFS of patients with SBC (versus no FANCD expression). Univariable and multivariable analyses demonstrated that BRCA1 expression may be an independent prognostic factor in the FBC group. In the SBC group, FANCD2 high expression and low ubiquitination levels were considered as independent prognostic factors. In conclusion, the present study suggested that BRCA1 and FANCD2 expression, and FANCD2 ubiquitination levels, may be considered of novel potential prognostic value in patients with BC.

SOX17 overexpression sensitizes chemoradiation response in esophageal cancer by transcriptional down-regulation of DNA repair and damage response genes

BackgroundPrognosis of esophageal squamous cell carcinoma (ESCC) patients is poor and the concurrent chemoradiation therapy (CCRT) provided to ESCC patients often failed due to resistance. Therefore, development of biomarkers for predicting CCRT response is immensely important. In this study, we evaluated the predicting value of SRY (sex determining region Y)-box 17 (SOX17) protein during CCRT and its dysregulation of transcriptional targets in CCRT resistance in ESCC.MethodsPyrosequencing methylation, RT-qPCR and immunohistochemistry assays were performed to examine the DNA methylation, mRNA expression and protein expression levels of SOX17 in endoscopic biopsy from a total of 70 ESCC patients received CCRT. Cell proliferation, clonogenic survival and xenograft growth were used to confirm the sensitization of ESCC cell line KYSE510 in response to cisplatin, radiation or CCRT treatment by SOX17 overexpression in vitro and in vivo. Luciferase activity, RT-qPCR and ChIP-qPCR assays were conducted to examine transcription regulation of SOX17 in KYSE510 parental, KYSE510 radio-resistant cells and their derived xenografts.ResultsHigh DNA methylation coincided with low mRNA and protein expression levels of SOX17 in pre-treatment endoscopic biopsy from ESCC patients with poor CCRT response. SOX17 protein expression exhibited a good prediction performance in discriminating poor CCRT responders from good responder. Overexpression of SOX17 sensitized KYSE510 radio-resistant cells to cisplatin, radiation or CCRT treatment in cell and xenograft models. Importantly, SOX17 transcriptionally down-regulated DNA repair and damage response-related genes including BRCA1, BRCA2, RAD51, KU80 DNAPK, p21, SIRT1, NFAT5 and REV3L in KYSE510 radio-resistant cells to achieve the sensitization effect to anti-cancer treatment. Low expression of BRCA1, DNAPK, p21, RAD51 and SIRT1 was confirmed in SOX17 sensitized xenograft tissues derived from radio-resistant ESCC cells.ConclusionsOur study reveals a novel mechanism by which SOX17 transcriptionally inactivates DNA repair and damage response-related genes to sensitize ESCC cell or xenograft to CCRT treatment. In addition, we establish a proof-of-concept CCRT prediction biomarker using SOX17 immunohistochemical staining in pre-treatment endoscopic biopsies to identify ESCC patients who are at high risk of CCRT failure and need intensive care.

Quantifying BRCA1 and BRCA2 mRNA Isoform Expression Levels in Single Cells.

BRCA1 and BRCA2 spliceogenic variants are often associated with an elevated risk of breast and ovarian cancers. Analyses of BRCA1 and BRCA2 splicing patterns have traditionally used technologies that sample a population of cells but do not account for the variation that may be present between individual cells. This novel proof of concept study utilises RNA in situ hybridisation to measure the absolute expression of BRCA1 and BRCA2 mRNA splicing events in single lymphoblastoid cells containing known spliceogenic variants (BRCA1c.671-2 A>G or BRCA2c.7988 A>T). We observed a large proportion of cells (>42%) in each sample that did not express mRNA for the targeted gene. Increased levels (average mRNA molecules per cell) of BRCA2 ∆17_18 were observed in the cells containing the known spliceogenic variant BRCA2c.7988 A>T, but cells containing BRCA1c.671-2 A>G were not found to express significantly increased levels of BRCA1 ∆11, as had been shown previously. Instead, we show for each variant carrier sample that a higher proportion of cells expressed the targeted splicing event compared to control cells. These results indicate that BRCA1/2 mRNA is expressed stochastically, suggesting that previously reported results using RT-PCR may have been influenced by the number of cells with BRCA1/2 mRNA expression and may not represent an elevation of constitutive mRNA expression. Detection of mRNA expression in single cells allows for a more comprehensive understanding of how spliceogenic variants influence the expression of mRNA isoforms. However, further research is required to assess the utility of this technology to measure the expression of predicted spliceogenic BRCA1 and BRCA2 variants in a diagnostic setting.

The antiestrogenic effects of black cohosh on BRCA1 and steroid receptors in breast cancer cells.

BackgroundBlack cohosh (BC) is an herbal remedy often used by women to treat symptoms associated with menopause. Research has shown that the molecular activity of BC is associated with estrogen receptor alpha (ER-α) regulation. Progesterone receptor (PR) expression is found to be consistent with ER expression and mutations in the BRCA1 gene, a tumor-suppressor gene, are known to be responsible for about 40%–45% of hereditary breast cancers.PurposeThe objective of this study was to determine the effects of BC alone, as well as in combination with hormones and antihormones, on cell viability and expression of ER-α, PR, and BRCA1 in both T-47D and MCF-7 cell lines.MethodsCells were cultured in charcoal-stripped serum prior to their treatment and subsequent protein extraction. Western blot analyses were performed following a Bio-Rad Bradford protein assay and SDS-PAGE gel electrophoresis, with ECL luminescence and Image Studio Lite software. Cellular viability assays were performed using propidium iodine (PI) staining, and the distribution of fluorescent structures was evaluated through confocal microscopy. RT-qPCR analysis was performed on extracted cellular RNA. All statistical analyses were performed using SPSS software, and data was subjected to Kruskal-Wallis testing, followed by post-hoc analysis using the Mann-Whitney U-test to determine the statistical significance of all findings.ResultsWestern blot analysis displayed significant alterations of ER-α, PR, and BRCA1 protein levels after 24-hour treatment with 80–500 μM BC. BC displayed a concentration-dependent decrease on ER-α and BRCA1 expression, with an 87% reduction of ER-α expression and a 43% of BRCA1 expression in T-47D cells compared to control. After six days of treatment with 400 μM BC, a 50% decrease in cell proliferation was observed. Following 24 hours of co-treatment with 400 μM BC and 10 nM E2, ER-α was downregulated by 90% and BRCA1 expression was reduced by 70% compared to control. The expression of PR, following the same treatment, exhibited similar effects. The proliferative effect of E2 was reduced in the presence of BC.ConclusionBlack Cohosh demonstrates substantial anti-cancer properties, and this study may significantly aid in the understanding of the molecular effects of BC on ER-α, PR, and BRCA1 in breast cancer cells.

The protective role of rs56103835 against breast cancer onset in the Iranian population.

BackgroundBreast cancer is one of the most common types of cancer among women and the highest cause of death due to cancer among women aged 40–45. SNPs can be used to identify disease‐related genes such as cancer as they can be genetic markers. Furthermore, SNPs in the molecular‐level miRNA structure are also associated with a set of cancers. Studies have shown that miR‐323b plays a tumor suppressor role by reducing the tissues and serum of the affected individuals. So far, no study regarding rs56103835 polymorphism in the precursor of miR‐323b has been conducted in the breast cancer. In this study, the association of this SNP with the incidence of breast cancer in the Iranian population has been investigated.MethodIn order to correlate rs56103835 polymorphism with breast cancer, 161 patients and 162 healthy people as the control group were examined. They had been homogenized based on their age and gender. The genotype of individuals for the polymorphism was determined by the PCR‐RFLP method. The association of this polymorphism with the risk of breast cancer, the age of the onset of disease, and pathological characteristics of the patients was then analyzed.ResultsThe findings showed that there is no significant correlation between the frequency of its genotypes among the healthy and patient populations while the TT genotype increased the age of the disease in patients, as compared to other genotypes (p = 0.035, OR = 0.487).Discussion and ConclusionThe C allele is likely to inhibit the expression of BRCA2 by interfering with the processing of this pre‐miRNA and increasing the expression of target genes such as BRCA2. Because one of the early onset genes in breast cancer is the BRCA2, the presence of any of C and T alleles can have a significant effect on the incidence of the disease. To further confirm this data, however, more molecular studies are needed.

Liver Kinase B1-A Potential Therapeutic Target in Hormone-Sensitive Breast Cancer in Older Women.

Background: The role of liver kinase B1 (LKB1), a serine/threonine kinase, has been described in the development of PeutzJagher’s syndrome, where a proportion (~45%) of patients have developed breast cancer in their lifetime. Cell line studies have linked LKB1 with oestrogen receptors (ER) and with the Adenosine monophosphate-activated protein kinase (AMPK) pathway for energy metabolism. However, limited studies have investigated protein expression of LKB1 in tumour tissues and its intracellular relationships. This study aimed to investigate the intracellular molecular relationships of LKB1 in older women with early operable primary breast cancer and its correlation with long-term clinical outcome. Methods: Between 1973 and 2010, a consecutive series of 1758 older (≥70 years) women with T0-2N0-1M0 breast carcinoma were managed in a dedicated facility. Of these, 813 patients underwent primary surgery, and 575 had good quality tumour samples available for tissue microarray construction. LKB1 was assessed in 407 cases by indirect immunohistochemistry (IHC). Tumours with 30% or more of cells with cytoplasmic LKB1 expression were considered positive. LKB1 expression was compared with tumour size, histological grade, axillary lymph node stage, ER, PgR, EGFR, HER2, HER3, HER4, BRCA1&2, p53, Ki67, Bcl2, Muc1, E-Cadherin, CD44, basal (CK5, CK5/6, CK14 and CK17) and luminal (CK7/8, CK18 and CK19) cytokeratins, MDM2 and MDM4, and correlated with long-term clinical outcome. Results: Positive LKB1 expression was seen in 318 (78.1%) patients, and was significantly associated with high tumour grade, high Ki67, over-expression of HER2, VEGF, HER4, BRCA2, MDM2 and negative expression of CD44 (p < 0.05). There was no significant correlation with tumour size, axillary lymph node status, ER, PgR, p53, basal or luminal cytokeratins, Bcl2, Muc1, EGFR, HER3, MDM4, E-cadherin and BRCA1. LKB1 did not show any significant influence on survival in the overall population; however, in those patients receiving adjuvant endocrine therapy for ER positive tumours, those with positive LKB1 had significantly better 5-year breast cancer specific survival when compared to those without such expression (93% versus 74%, p = 0.03). Conclusion: LKB1 expression has shown association with poor prognostic factors in older women with breast cancer. However, LKB1 expression appears to be associated with better survival outcome among those patients receiving adjuvant endocrine therapy. Further research is required to explore its potential role as a therapeutic target.

Prognostic effects of abnormal DNA damage response protein expression in breast cancer.

We aimed to explore the expression of DNA damage response machinery proteins and their integrated prognostic value in different subgroups of breast cancer. Expression of NBS1, BRCA1, BRCA2, ATM, and p53 was determined by immunohistochemistry in 419 surgically resected breast tumors. Loss of NBS1, BRCA1, ATM, and abnormal p53 expression was significantly associated with lower disease-free survival rates. Abnormal DNA damage response protein expression, defined as loss of any one of NBS1, BRCA1, ATM, and/or abnormal p53 expression, was observed in 258 of 399 evaluable cases (64.7%) and was significantly associated with higher tumor grade, larger tumor size, and ER-negative, and/or PR-negative status. Most patients with luminal B (86.1%), HER2-enriched (94.4%), and triple-negative (86.8%) breast cancers had abnormal DNA damage response protein expression. In contrast, abnormal DNA damage response protein expression was found in only 53.8% of luminal A tumors. Abnormal DNA damage response protein expression was associated with significantly lower 5-year disease-free survival rates in all patients (95.6% vs. 84.8%, p = 0.001), as well as in the luminal A subgroup (97.4% vs. 89.0%, p = 0.011). In multivariate analysis, abnormal DNA damage response protein expression remained an independent predictor of shorter disease-free survival for luminal A subtype (hazard ratio 3.14, 95% confidence interval 1.16-8.47; p = 0.024). Abnormal DNA damage response protein expression is found in most luminal B and HER2-enriched breast cancers as frequently as in triple-negative breast cancer. In the luminal A subtype, abnormal DNA damage response protein expression is an independent prognostic marker.

Human papilloma virus and breast cancer: the role of inflammation and viral expressed proteins

BackgroundBreast cancer is currently the most common neoplasm diagnosed in women globally. There is a growing body of evidence to suggest that human papillomavirus (HPV) infection may play a key role in invasiveness of breast cancer. The aim of this study was to determine the presence of HPV in patients with breast cancer and its possible association with cancer progression.MethodsBreast specimens were collected from 72 patients with breast cancer and 31 healthy controls. The presence of HPV was investigated by polymerase chain reaction (PCR) and genotyping was performed for positive cases. We also evaluated the viral factors such as E6, E2, and E7 in HPV positive cases. Enzyme-linked immunosorbent assay (ELISA (and Real-time PCR techniques were used to measure the expression level of anti-carcinogenic genes, such as p53, retinoblastoma (RB), breast and ovarian cancer susceptibility gene (BRCA1, BRCA2) and inflammatory cytokines, including tumor necrosis factor α (TNF-α), transforming growth factor β (TGF-β), nuclear factor-kB (NF-kB), and different interleukins [ILs] (IL-1,IL6, and IL-17).ResultsThe HPV DNA was detected in 48.6% of breast cancer samples, whereas only 16.1% of controls were positive for HPV. We observed statistically significant differences between breast cancer patients and HPV presence (P = 0.003). HPV type 18 was the most prevalent virus genotype in patients. The expression of P53, RB, BRCA1, and BRCA2 were decreased in patients with HPV-positive breast cancer as compared to HPV-negative breast cancer and healthy controls. (All P-values were less than 0.05). The presence of the HPV was associated with increased inflammatory cytokines (IL-1, IL-6, IL-17, TGF-β, TNF-α, and NF-kB) and tumor progression.ConclusionThe present study demonstrated that HPV infection may implicate in the development of some types of breast cancer.

Expression of HPV-induced DNA Damage Repair Factors Correlates With CIN Progression.

Human papillomaviruses (HPVs) are DNA viruses with epithelial tropism. High-risk types of HPV are the causative agents of the majority of cervical cancers and are responsible for a number of other anogenital as well as oropharyngeal cancers. The life cycle of HPV is closely linked to the differentiation state of its host cell and is dependent on the activation of specific pathways of the DNA damage response. Several proteins from the ataxia telangiectasia mutated and the ataxia telangiectasia mutated and Rad3-related DNA repair pathways, which are essential for maintaining genomic stability in cells, are upregulated in HPV-positive cells and are required for viral replication. Our studies examine the expression of 5 such DNA repair factors-pCHK2, pCHK1, FANCD2, BRCA1, and H2AX-in cervical specimens from patients diagnosed with low-grade, intermediate-grade, or high-grade lesions. The percentage of cells expressing pCHK2, pCHK1, FANCD2, and BRCA1 is significantly higher in high-grade squamous intraepithelial lesions compared with that of either low-grade squamous intraepithelial lesions or normal tissue, particularly in differentiated cell layers. In addition, the distribution of this staining throughout the epithelium is altered with increasing lesion grade. This study characterizes the expression of pCHK2, pCHK1, FANCD2, H2AX and BRCA1 during cervical cancer progression and provides additional insight into the role of these DNA damage response proteins in viral transformation.

BRCA1 and Breast Cancer: a Review of the Underlying Mechanisms Resulting in the Tissue-Specific Tumorigenesis in Mutation Carriers.

Since the first cloning of BRCA1 in 1994, many of its cellular interactions have been elucidated. However, its highly specific role in tumorigenesis in the breast tissue—carriers of BRCA1 mutations are predisposed to life-time risks of up to 80%—relative to many other tissues that remain unaffected, has not yet been fully enlightened. In this article, we have applied a universal model of tissue-specificity of cancer genes to BRCA1 and present a systematic review of proposed concepts classified into 4 categories. Firstly, tissue-specific differences in levels of BRCA1 expression and secondly differences in expression of proteins with redundant functions are outlined. Thirdly, cell-type specific interactions of BRCA1 are presented: its regulation of aromatase, its interaction with Progesterone- and receptor activator of nuclear factor-κB ligand-signaling that controls proliferation of luminal progenitor cells, and its influence on cell differentiation via modulation of the key regulators jagged 1-NOTCH and snail family transcriptional repressor 2. Fourthly, factors specific to the cell-type as well as the environment of the breast tissue are elucidated: distinct frequency of losses of heterozygosity, interaction with X inactivation specific transcript RNA, estrogen-dependent induction of genotoxic metabolites and nuclear factor (erythroid-derived 2)-like 2, and regulation of sirtuin 1. In conclusion, the impact of these concepts on the formation of hormone-sensitive and -insensitive breast tumors is outlined.

The immunohistochemical Evaluation of BRcA2 Expression with HPV infection in a Group of iraqi Women with cervical carcinoma

The immunohistochemical Evaluation of BRcA2 Expression with HPV infection in a Group of iraqi Women with cervical carcinoma

How latent viruses cause breast cancer: An explanation based on the microcompetition model.

Most breast cancer cases show a decrease in the concentration of the breast cancer type 1 susceptibility protein (BRCA1). However, only a small portion of these cases have a mutated BRCA1 gene. Although many attempts have been made to identify the reason for the decrease in BRCA1 concentration in sporadic, non-heritable breast cancer cases, the cause is still unknown. In this review, we use the Microcompetition Model to explain how certain latent viruses, which are frequently detected in breast cancer tumors, can decrease the expression of the BRCA1 gene and cause the development of breast tumors.

XPC deficiency leads to centrosome amplification by inhibiting BRCA1 expression upon cisplatin-mediated DNA damage in human bladder cancer

Xeroderma pigmentosum group C (XPC) is a well-known DNA damage recognition protein. Defects in XPC lead to carcinogenesis and progression of many human cancers. In the current study, we defined a novel, important role of XPC in preventing centrosome amplification during cisplatin-mediated DNA damage response. From experiments with human bladder cancer tissue, urothelial tissue from Xpc knockout mice and XPC-silenced cell lines, we found that attenuated XPC expression was associated with increased centrosome amplification in human bladder cancer. A significant increase in centrosome amplification was observed in XPC-silenced cells upon cisplatin treatment. XPC deficiency leads to reduced BRCA1 expression via upregulating its transcriptional repressor, Pit-1. The BRCA1 downregulation results in more DNA double strand breaks accumulation and persistent activation of the ATM-Chk1/Chk2 signaling, resulting in a prolonged G2/M arrest during which centrosome can over-duplicate and lead to centrosome amplification. XPC complementation in silenced cells could reduce Pit-1 expression, increase BRCA1 expression and recover the status of centrosome amplification. Our study reveals a new function for XPC in preventing chromosomal instability, providing new information on cancer chemotherapy and potential clinical significance for cancer management.

Association Between Impairment of DNA Double Strand Break Repair and Decreased Ovarian Reserve in Patients With Endometriosis.

Background: Repair of DNA double strand break (DSB) is an important mechanism for maintaining genetic stability during a DNA damage event. Although, a growing body of recent evidence suggests that DNA DSBs and related repair mechanisms may be important in ovarian aging and in various cancers, there are few reports in endometriosis. We, therefore, examined expression levels of genes pertaining to DNA DSB repair in patients with endometriosis to assess the potential effects on ovarian reserves.Materials and methods: A total of 69 women undergoing laparoscopic surgery for endometriosis and other benign conditions was included; endometriosis group (n = 38) vs. controls (n = 31). DNA DSBs in endometrial and ovarian tissues of both groups were compared via immunohistochemistry, aimed at γ-H2AX expression. To gauge genotoxin-induced DNA DSBs in endometrial stromal cells, γ-H2AX expression was determined by western blot after H2O2 treatment of cultured endometrial stromal cells (endometriosis group and controls) and Ishikawa cell-line cultures. Endometrial and ovarian tissue levels of BRCA1, BRCA2, Rad51, and ATM (ataxia-telangiectasia mutated) mRNA expression were also compared. Correlations between expression levels of genes of interest and serum anti-müllerian hormone (AMH) levels were assessed as well.Results: Expression of γ-H2AX in immunostained endometrial and ovarian tissue preparations was greater in the endometriosis group, compared with controls. After H2O2 treatment, γ-H2AX expression levels were also significantly greater in cultured stromal cells of the endometriosis group and in the Ishikawa cell line than in controls. Endometrial expression of BRCA1 and Rad51 mRNA proved significantly lower in the endometriosis group (vs. controls), as did ovarian expression of BRCA1 and BRCA2 mRNA. Serum AMH concentration showed a significant correlation with ovarian BRCA1 mRNA expression in women with endometriosis (p = 0.03).Conclusions: In women with endometriosis, expression levels of various genes implicated in DSB repair are decreased and ovarian BRCA1 expression correlates with

Effect of AR antagonist combined with PARP1 inhibitor on sporadic triple-negative breast cancer bearing AR expression and methylation-mediated BRCA1 dysfunction

Triple-negative breast cancer (TNBC) patients usually present worse clinical outcomes due to their high heterogeneity. The purpose of our study is to investigate the prognostic role of AR and BRCA1 expression in sporadic TNBC patients, and effect of AR blockade and PARP1 inhibitor for TNBC patients who characterized by positive-AR expression and BRCA1 inactivation or dysfunction. In our present study, we found that AR is expressed in 43.6% and 34.0% of TNBC tissues, when 1% or 10% staining was used as the threshold for AR positivity, respectively. When 1% staining was used as the threshold, AR expression indicates a poor disease-free survival (DFS) of TNBC patients. TNBC patients with negative BRCA1 show a poor DFS, and BRCA1 suppression is associated with the methylation status of its promoter. Interestingly, BRCA1-/AR + TNBC patients have shorter DFS than other TNBC patients regardless of the threshold for AR positivity. AR antagonists MDV3100 enhances the PARP1 inhibitor Olaparib-mediated decrease of cell viability in AR-positive/BRCA1-inactivated cells in vitro and in vivo. Our results suggested that combination of AR blockade and PARP1 inhibitor may be a potential strategy for sporadic TNBC patients who characterized by positive-AR expression and BRCA1 inactivation or dysfunction.

Linc01638 Promotes Tumorigenesis in HER2+ Breast Cancer.

BackgroundLong non‐coding RNAs play crucial roles in various biological activities and diseases. The role of long intergenic non‐coding RNA01638 (linc01638) in breast cancer, espe-cially in HER2-positive breast cancer, remains largely unknown.ObjectiveTo investigate the effect of linc01638 on tumorigenesis in HER2-positive breast cancer.MethodsWe first used qRT-PCR to detect linc01638 expression in HER2-positive breast cancer cells and tissues. Then we analyzed the effects of linc01638 expression in HER2-positive breast cancer cells through cell apoptosis assay, cell proliferation assay, colony formation assay, and cell invasion assay. We conducted mouse xenograft model to further confirm the role of linc01638 in HER2-positive breast cancer. Moreover, we used Western blot and IHC analysis to access the effect of linc01638 on DNMTs, BRCA1 and PTEN expressions in transplanted tumors.ResultsLinc01638 was found to be remarkably overexpressed in HER2-positive breast cancer cells and tissues. Suppression of linc01638 enhanced cell apoptosis, as well as inhibited the growth and in-vasiveness of HER2-positive breast cancer cells in vitro and tumor progression and metastasis in vivo. Furthermore, inhibition of linc01638 by shRNA attenuated expression of DNMT1, DNMT3a, and DNMT3b, and promoted expression of BRCA1 and PTEN in HER2-positive breast cancer cells and mouse xenograft models.ConclusionLinc01638 might be a promising biomarker and therapeutic target for treatment of HER2-positive breast cancer.

Histopathological patterns of primary malignant ovarian neoplasms in different age groups in Almadinah Almunawwarah region, KSA.

ObjectivesIn the literature, the epidemiological pattern of ovarian neoplasms in different age groups in the Almadinah Almunawwarah region in KSA has not been completely elucidated. Moreover, an unusually frequent diagnosis of adult granulosa cell tumour (AGCT) has been observed in patients in Almadinah Almunawwarah, KSA. This study aimed to describe the pattern of ovarian neoplasms in different age groups in the Almadinah Almunawwarah region with particular emphasis on AGCT.MethodsHistopathological records of all ovarian specimens diagnosed from 2011 January to 2016 December were collected from the Maternity and Children Hospital in Almaadinah Almunawwarah, KSA. Hematoxylin and eosin (HE)-stained microscopic slides of serous and mucinous epithelial borderline neoplasms and of malignant epithelial, sex cord-stromal and germ line neoplasms were identified and examined. The tissue sections from the AGCT were stained immunohistochemically with BRCA-1 antibody.ResultsA total of 301 ovarian specimens were obtained. Of the specimens, 217 (72%) were neoplastic and 84 (28%) were non-neoplastic. In total, 135 (63%) of the neoplastic specimens were benign, 16 (7%) were borderline tumours, and 66 (30%) were malignant tumours. Moreover, 41 (62%) of the malignant tumours were surface epithelial carcinomas, 17 (26%) were sex cord-stromal tumours, and 8 (12%) were germ cell tumours. The incidence of AGCT was unusually high, which accounts for 26% (16/66) of all malignant ovarian neoplasms. Altered BRCA-1 expression was observed in only two specimens.ConclusionIn this study, malignant ovarian neoplasms accounted for 30% of all neoplastic ovarian specimens, and the incidence of AGCT was remarkable. Such tumours did not show a significantly altered expression of BRCA-1. Further studies must be conducted to explore the underlying molecular causes of this condition.