BRCA1 is a breast cancer susceptibility gene that is down-regulated in a significant proportion of sporadic breast cancers. BRCA1 is posttranscriptionally regulated by RNA-binding proteins, the identities of which are unknown. HuR is an RNA binding protein implicated in posttranscriptional regulation of many genes and is overexpressed in sporadic breast cancer. To investigate the possibility that these two molecules are functionally linked in breast cancer, we performed bioinformatic analysis of the BRCA1 3 untranslated region (UTR), RNA-protein assays with the HuR protein and the BRCA1 3UTR, and immunohistochemical analysis of a cohort of breast tumors using antibodies against BRCA1 and HuR. Here, we describe the identification of two predicted HuR-binding sites in the BRCA1 3UTR, one of which binds specifically to HuR. We also show that this interaction is disrupted by single nucleotide substitutions in the BRCA1 3UTR and that endogenous HuR protein associates with BRCA1 transcripts in ...
Given how BRCA2 is believed to function as a tumour suppressor, assays related to DNA repair are directly relevant to predicting the impact of BRCA2 variants on cancer risk and therapeutic response. Additionally, such assays have demonstrated high sensitivity and specificity for predicting known benign and pathogenic variants. For these reasons, DNA repair-related assays are considered here.21 Since DNA repair-related domains are distributed throughout BRCA2, as discussed earlier, such assays should be based on expression of full-length BRCA2. BRCA2 is even larger than BRCA1 (the protein is ~390 kDa and the cDNA is 10 254 bp). Thus, it has been difficult to express full-length BRCA2 in human cells using a cDNA.69 73 As such, some functional studies of BRCA2 VUS have been based on heterologous expression of full-length BRCA2 variants in mouse ESCs using BACs.71 72 These studies, in the laboratory of Shyam Sharan, focused on VUS in the N-terminal PALB2-binding domain and the C-terminal DBD, where ...
Breast Cancer is very common among Canadians. The Canadian Breast Cancer Foundation reported in 2014 " 1 in 9 women in Canada is expected to develop breast cancer during her lifetime." Today we are focusing on the genetic aspects of developing breast cancer in the body.. BRCA1 and BRCA2 genes - BRCA1 and BRCA 2 known, as a Breast Cancer Susceptibility Gene 1 and Breast Cancer Susceptibility Gene 2 are human genes and works as tumor suppressors.. How BRCA1 and BRCA2 connect to cancer? When any of those genes mutate, it causes DNA damage and it might not be able to repair properly, and as a results cell can develop additional genetic alterations. Inherited mutations in BRCA1 and BRCA2 then increase the risk of breast and ovarian cancer.. NOTE: BRCA1 and BRCA2 mutations can be inherited from a persons mother or father. Anyone who has inherited a BRCA1 or BRCA2 mutation could be an increase risk of developing breast and ovarian cancer.. Breast cancer statistics - Breast Cancer Society of Canada has ...
TY - JOUR. T1 - Inhibition of BRCT(BRCA1)-phosphoprotein interaction enhances the cytotoxic effect of olaparib in breast cancer cells. T2 - A proof of concept study for synthetic lethal therapeutic option. AU - Pessetto, Ziyan Yuan. AU - Yan, Ying. AU - Bessho, Tadayoshi. AU - Natarajan, Amarnath. PY - 2012/7. Y1 - 2012/7. N2 - Synthetic lethal therapeutic strategy using poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor olaparib in carriers of BRCA1 or BRCA2 mutation has shown promise in clinical settings. Since ≤5 % of patients are BRCA1 or BRCA2 mutation carriers, small molecules that functionally mimic BRCA1 or BRCA2 mutations will extend the synthetic lethal therapeutic option for non-mutation carriers. Here we provide proof of principle for this strategy using a BRCA1 inhibitor peptide 2 that targets the BRCT(BRCA1)-phosphoprotein interaction and mimics the M177R/K BRCA1 mutation. Reciprocal immunoprecipitation and immunoblotting of BRCA1 and Abraxas was used to ...
About 5% to 10% of breast cancers are thought to be hereditary, caused by abnormal genes passed from parent to child.. Genes are particles in cells, contained in chromosomes, and made of DNA (deoxyribonucleic acid). DNA contains the instructions for building proteins. And proteins control the structure and function of all the cells that make up your body.. Most inherited cases of breast cancer are associated with two abnormal genes: BRCA1 (BReast CAncer gene one) and BRCA2 (BReast CAncer gene two).. Everyone has BRCA1 and BRCA2 genes. The function of the BRCA genes is to repair cell damage and keep breast cells growing normally. But when these genes contain abnormalities or mutations that are passed from generation to generation, the genes dont function normally and breast cancer risk increases. Abnormal BRCA1 and BRCA2 genes may account for up to 10% of all breast cancers, or 1 out of every 10 cases.. Having an abnormal BRCA1 or BRCA2 gene doesnt mean you will be diagnosed with breast cancer. ...
Given that breast cancers in germline BRCA1 carriers are predominantly estrogen-negative and triple-negative, it has been suggested that women diagnosed with triple-negative breast cancer (TNBC) younger than 50 years should be offered BRCA1 testing, regardless of family cancer characteristics. However, the predictive value of triple-negative breast cancer, when taken in the context of personal and family cancer characteristics, is unknown. The aim of this study was to determine whether TNBC is a predictor of germline BRCA1 mutations, in the context of multiple predictive factors. Germline mutations in BRCA1 and BRCA2 were analyzed by Sanger sequencing and multiple ligation-dependent probe amplification (MLPA) analysis in 431 women from the Malaysian Breast Cancer Genetic Study, including 110 women with TNBC. Logistic regression was used to identify and to estimate the predictive strength of major determinants. Estrogen receptor (ER) and phosphatase and tensin homologue (PTEN) status were assessed and
SNPedia currently contains 2606 BRCA1 SNPs and 3099 BRCA2 SNPs. Some of the variations in these genes are linked to Breast cancer and ovarian cancer, and other variations are benign. See also BRCA1 and BRCA2 for individual gene discussions and links. Microarray platforms used by DTC genomics testing companies such as FamilyTree DNA and 23andMe usually test a fraction of the known BRCA1 or BRCA2 SNPs, typically, the most common ones. While DTC genomics testing may lead to useful results, it is not a substitute for the full genetic panel testing or gene sequencing that may be warranted by a family history of breast cancer. The percent of known BRCA1 and BRCA2 syndrome disease-causing mutations that are tested by several companies is shown in the following table: ...
Men with prostate cancer who are carriers of the BRCA2 gene mutation have significantly increased mortality rates.. The study identified 938 families with the BRCA2 mutation, of which 277 (29.5%) contained one or more cases of prostate cancer, with a total of 434 cases. Of these, 67 men were found to carry the familial BRCA2 mutation and 116 were probable mutation carriers. A comparison group of men with the BRCA1 mutation was also identified. Of 1,735 families, 316 contained one or more cases of prostate cancer (18.2%), with a total of 457 cases. Of these, 37 carried the BRCA1 mutation and 82 men were probable carriers. The average age at diagnosis was similar for the two groups.. Survival analysis was performed to establish the overall survival of BRCA2 carriers with prostate cancer and relative survival compared with BRCA1 carriers. The median survival time was 4.0 years for the BRCA2 group compared with 8.0 years for the BRCA1 group, and the risk of mortality was found to be 70% greater in ...
Ataxia-telangiectasia mutation (ATM) has previously been shown to be necessary for the phosphorylation of BRCA1 to occur in response to gamma-irradiation, and capable of directly phosphorylating BRCA1 in vitro (see additional information). This paper indicates that ATM can also cause the phosphorylation of BRCA1 by activating the hCds1/CHK2 kinase, for which BRCA1 is a substrate. Phosphorylation of BRCA1 in response to other genotoxins appears to be independent of ATM (Scully et al, Cell 1997, 90: 425-435 [Abstract]). ATM-independent activation of hCds1/CHK2 may explain how some of these other genotoxins cause BRCA1 phosphorylation.. The ATM-hCds1/CHK2-BRCA1 DNA damage response pathway is clearly important for tumour suppression since heterozygous carriers of mutant BRCA1, ATM and hCds1/hCHK2 genes (see additional information) have all been reported to be predisposed to breast cancer. ...
TY - JOUR. T1 - Genetic testing in an ethnically diverse cohort of high-risk women. T2 - A comparative analysis of BRCA1 and BRCA2 mutations in American families of European and African ancestry. AU - Nanda, Rita. AU - Schumm, L. Philip. AU - Cummings, Shelly. AU - Fackenthal, James D.. AU - Sveen, Lise. AU - Ademuyiwa, Foluso. AU - Cobleigh, Melody. AU - Esserman, Laura. AU - Lindor, Noralane Morey. AU - Neuhausen, Susan L.. AU - Olopade, Olufunmilayo I.. PY - 2005/10/19. Y1 - 2005/10/19. N2 - Context: Ten years after BRCA1 and BRCA2 were first identified as major breast cancer susceptibility genes, the spectrum of mutations and modifiers of risk among many ethnic minorities remain undefined. Objectives: To characterize the clinical predictors, spectrum, and frequency of BRCA1 and BRCA2 mutations in an ethnically diverse high-risk clinic population and to evaluate the performance of the BRCAPRO statistical model in predicting the likelihood of a mutation. Design, Setting, and Participants: ...
Modular domains of proteins are important in cellular signaling processes. Eukaryotic cells are constantly undergoing DNA damage due to exogenous and endogenous sources of damage. The DNA damage response (DDR) involves a complex network of signaling events mediated by modular domains such as the BRCT (BRCA1 C-terminal) domains. Therefore, proteins containing BRCT domains are important for DNA damage detection and signaling. In this dissertation, we focus on two BRCT-containing proteins BRCA1 and PAXIP1. BRCA1 is a gene that is known to be associated with increased risk of hereditary breast and ovarian cancer. Germline variants of BRCA1 are assessed to determine lifetime risk of developing breast and ovarian cancer. This is performed by genetic testing of the BRCA1 sequence and the variants can be classified as pathogenic, non-pathogenic or variants of unknown significance (VUS). Using family history, segregation analysis, co-occurrence and tumor pathology, certain variants have been classified as either
The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific
Abnormalities caused by targeted disruption of the Brca2 gene include increased sensitivity to DNA damage induced by ionizing irradiation, UV light, and other genotoxic agents (27, 33, 34). The accumulation of double-strand DNA breaks and chromosomal abnormalities combined with the lack of obvious checkpoint or apoptotic response abnormalities in Brca2 mutant cells have implied a role of BRCA2 in DNA repair (33, 34). Recent findings that BRCA2 and RAD51 interact in vitro have suggested further that BRCA2 may be involved in RAD51-mediated repair pathways (27, 35, 36). In this study, we identified the BRCA2 gene product as a 460-kDa nuclear phosphoprotein that forms a complex with RAD51 in vivo. While this manuscript was in preparation, Chen et al. (44) reported detection of BRCA2 as a nuclear protein, consistent with our findings. They also reported detection of immunocomplexes containing BRCA2 and RAD51 (44). Our findings established that a major fraction of endogenous RAD51 is associated with ...
article{81b520fa-fde6-40e1-9977-b09909f3e717, abstract = {Inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose carriers to breast and ovarian cancer. The authors have identified a mutation in BRCA2, 7845+1G > A (c.7617+1G > A), not previously regarded as deleterious because of incorrect mapping of the splice junction in the originally published genomic reference sequence. This reference sequence is generally used in many laboratories and it maps the mutation 16 base pairs inside intron 15. However, according to the recent reference sequences the mutation is located in the consensus donor splice sequence. By reverse transcriptase analysis, loss of exon 15 in the final transcript interrupting the open reading frame was demonstrated. Furthermore, the mutation segregates with a cancer phenotype in 18 Danish families. By genetic analysis of more than 3,500 Danish breast/ovarian cancer risk families, the mutation was identified as the most common BRCA2 mutation in West ...
To explore the relation of BRCA1 to these foci, we assayed, for IRIF (17), HCC1937 cells that express a COOH-terminally truncated BRCA1 protein (19). BRCA1 foci were diminished in these cells, and the nuclear staining of BRCA1 was homogenous, albeit much dimmer, in HCC1937 cells regardless of treatment (Fig. 3B). Interestingly, hRad50, hMre11, and p95 IRIF were dramatically reduced in HCC1937 cells. Most of the irradiated cells displayed a diffuse nuclear pattern of hRad50, hMre11, or p95 immunostaining similar to that seen in untreated HCC1937 cells. In contrast, IRIF that were positive for hRad51 antibodies were readily and efficiently detected in both T24 and HCC1937 cells (Fig. 3B).. In addition to BRCA1 mutation, HCC1937 also harbors many other genetic changes (19). To determine whether the BRCA1 deficiency was responsible for the defect in IRIF formation, we transiently transfected hemagglutinin (HA)-tagged wild-type BRCA1 into HCC1937 cells and irradiated cells 40 hours later. Of the ...
Germline mutations in the tumor-suppressor gene BRCA2 predispose to breast and ovarian cancer. BRCA2 plays a well-established role in maintaining genome stability by regulating homologous recombination. BRCA2 has more recently been implicated in cytokinesis, the final step of cell division, but the molecular basis for this remains unknown. We have used time-lapse microscopy, recently developed cytokinesis assays and BAC recombineering (bacterial artificial chromosome recombinogenic engineering to investigate the function and localization of BRCA2 during cell division. Our analysis suggests that BRCA2 does not regulate cytokinesis in human cells. Thus, cytokinesis defects are unlikely to contribute to chromosomal instability and tumorigenesis in BRCA2-related cancers. ...
Mutation of BRCA1 and BRCA2 is the most common cause of inherited breast and ovarian cancer. Genetic screens to detect carriers of variants can aid in cancer prevention by identifying individuals with a greater cancer risk and can potentially be used to predict the responsiveness of tumours to therapy. Frequently, classification cannot be performed based on traditional approaches such as segregation analyses, including for many missense variants, which are therefore referred to as variants of uncertain significance (VUS). Functional assays provide an important alternative for classification of BRCA1 and BRCA2 VUS. As reviewed here, both of these tumour suppressors promote the maintenance of genome stability via homologous recombination. Thus, related assays may be particularly relevant to cancer risk. Progress in implementing functional assays to assess missense variants of BRCA1 and BRCA2 is considered here, along with current limitations and the path to more impactful assay systems. While ...
The breast cancer susceptibility gene 1 (BRCA1) has been well established as a tumor suppressor and functions primarily by maintaining genome integrity. Genome stability is compromised when cells are exposed to oxidative stress. Increasing evidence suggests that BRCA1 regulates oxidative stress and this may be another mechanism in preventing carcinogenesis in normal cells. Oxidative stress caused by reactive oxygen species (ROS) is implicated in carcinogenesis and is used strategically to treat human cancer. Thus, it is essential to understand the function of BRCA1 in oxidative stress regulation. In this review, we briefly summarize BRCA1s many binding partners and mechanisms, and discuss data supporting the function of BRCA1 in oxidative stress regulation. Finally, we consider its significance in prevention and/or treatment of BRCA1-related cancers.
The breast cancer susceptibility gene 1 (BRCA1) has been well established as a tumor suppressor and functions primarily by maintaining genome integrity. Genome stability is compromised when cells are exposed to oxidative stress. Increasing evidence suggests that BRCA1 regulates oxidative stress and this may be another mechanism in preventing carcinogenesis in normal cells. Oxidative stress caused by reactive oxygen species (ROS) is implicated in carcinogenesis and is used strategically to treat human cancer. Thus, it is essential to understand the function of BRCA1 in oxidative stress regulation. In this review, we briefly summarize BRCA1s many binding partners and mechanisms, and discuss data supporting the function of BRCA1 in oxidative stress regulation. Finally, we consider its significance in prevention and/or treatment of BRCA1-related cancers.
A womans lifetime chance of developing breast and/or ovarian cancer is greatly increased if she inherits an altered BRCA1 or BRCA2 gene. Women with an inherited alteration in one of these genes have an increased risk of developing these cancers at a young age (before menopause), and often have multiple close family members with the disease. These women may also have an increased chance of developing colon cancer. Men with an altered BRCA1 or BRCA2 gene also have an increased risk of breast cancer (primarily if the alteration is in BRCA2), and possibly prostate cancer. Alterations in the BRCA2 gene have also been associated with an increased risk of lymphoma, melanoma, and cancers of the pancreas, gallbladder, bile duct, and stomach in some men and women.. According to estimates of lifetime risk, about 13.2 percent (132 out of 1,000 individuals) of women in the general population will develop breast cancer, compared with estimates of 36 to 85 percent (360-850 out of 1,000) of women with an ...
LOH of three intragenic BRCA1 SNPs (2201C/T, 2430T/C, and 2731C/T) that flank the mutation site was confirmed in both the primary and recurrent tumors ( Fig. 3A and B, and data not shown), indicating that contamination by nontumor cells was negligible and that both the primary and recurrent tumors had lost one BRCA1 allele. Intriguingly, in the primary tumor, both wild-type BRCA1 sequence and BRCA1 sequence with 2594delC were detected ( Fig. 3A and B). Careful laser microdissection of a separate second sample of this tumor revealed the same result. The presence of both wild-type BRCA1 sequence and mutant sequence on one allele in the primary tumor suggests that genetic reversion (back mutation to wild-type) occurred on one copy of the mutant allele. We speculate that the presence of the genetically reverted wild-type allele in the primary tumor contributed to the unusual initial platinum resistance of this tumor. The selective pressure for the genetically reverted tumor cells in the primary ...
TY - JOUR. T1 - Efficacy versus effectiveness of clinical genetic testing criteria for BRCA1 and BRCA2 hereditary mutations in incident breast cancer. AU - Nilsson, Martin P.. AU - Winter, Christof. AU - Kristoffersson, Ulf. AU - Rehn, Martin. AU - Larsson, Christer. AU - Saal, Lao H.. AU - Loman, Niklas. PY - 2017/4. Y1 - 2017/4. N2 - Increasing evidence supports the benefit of identifying BRCA1 and BRCA2 germline mutations in early breast cancer. Selection of patients for genetic testing is based on defined criteria taking individual and family history related factors into account. It is important to make a distinction between efficacy and effectiveness of BRCA testing criteria. Efficacy can be defined as the performance under ideal circumstances, whereas effectiveness refers to its real life performance. To allow for an unbiased and detailed evaluation of efficacy and effectiveness of the Swedish BRCA testing criteria, we retrospectively analyzed a prospectively collected cohort of 273 breast ...
If a parent is determined to have a germline RB1 cancer-predisposing mutation either by positive family history, by an eye examination that reveals a retinoblastoma-associated eye lesion, or by molecular genetic testing that reveals the presence of a cancer-predisposing RB1 mutation, the risk to each sib of the index case is 50% (or lower if the carrier parent is a mutational mosaic) of inheriting the cancer-predisposing RB1 mutation. Given the approximately 99% penetrance of most RB1 cancer-predisposing mutations, the actual risk for retinoblastoma in these individuals is about 50% (or lower if the carrier parent is a mutational mosaic). (Note: In rare families with "familial-low penetrance retinoblastoma," the risk of tumor development is less than 40 ...
The BRCA2 and MRE11 proteins participate in the repair of double-strand DNA breaks by homologous recombination. Germline BRCA2 mutations predispose to ovarian, breast and pancreatic cancer, while a germline MRE11 mutation is associated with an ataxia telangiectasia-like disorder. Somatic mutations of BRCA2 are rare in typical sporadic cancers. In tumors having microsatellite instability (MSI), somatic truncating mutations in a poly [A] tract of BRCA2 are reported on occasion. We analyzed gastrointestinal MSI cancers by whole gene BRCA2 sequencing, finding heterozygous truncating mutations in seven (47%) of 15 patients. There was no cellular functional defect in RAD51 focus-formation in three heterozygously mutated lines studied, although other potential functions of the BRCA2 protein could still be affected. A prior report of mutations in primary MSI tumors affecting the IVS5-(5-15) poly [T] tract of the MRE11 gene was confirmed and extended by analysis of the genomic sequence and protein expression in
Loss of heterozygosity data from familial tumors suggest that BRCA1, a gene that confers susceptibility to ovarian and early-onset breast cancer, encodes a tumor suppressor. The BRCA1 region is also subject to allelic loss in sporadic breast and ovarian cancers, an indication that BRCA1 mutations may occur somatically in these tumors. The BRCA1 coding region was examined for mutations in primary breast and ovarian tumors that show allele loss at the BRCA1 locus. Mutations were detected in 3 of 32 breast and 1 of 12 ovarian carcinomas; all four mutations were germline alterations and occurred in early-onset cancers. These results suggest that mutation of BRCA1 may not be critical in the development of the majority of breast and ovarian cancers that arise in the absence of a mutant germline allele ...
Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, Bell R, Rosenthal J, Hussey C, Tran T, McClure M, Frye C, Hattier T, Phelps R, Haugen-Strano A, Katcher H, Yakumo K, Ghalami Z, Shaffer D, Stone S, Bayer S, Wray C, Bogden R, Dayananth P, Ward J, Tonin P, Narod S, Pam K, Bristow PK, Norris FH, Helvering L, Morrison P, Rosteck P, Lai M, Barrett JC, Lewis C, Neuhausen S, Cannon-Albright L, Goldgar D, Wiseman R, Kamb A, Skolnick MH. 1994. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266: 66-71 ...
Breast cancer 1, early onset (BRCA1) expression is often reduced in sporadic breast tumors, even in the absence of BRCA1 genetic modifications, but the molecular basis for this is unknown. In this study, we identified homeobox A9 (HOXA9) as a gene frequently downregulated in human breast cancers and tumor cell lines and noted that reduced HOXA9 transcript levels associated with tumor aggression, metastasis, and patient mortality. Experiments revealed that loss of HOXA9 promoted mammary epithelial cell growth and survival and perturbed tissue morphogenesis. Restoring HOXA9 expression repressed growth and survival and inhibited the malignant phenotype of breast cancer cells in culture and in a xenograft mouse model. Molecular studies showed that HOXA9 restricted breast tumor behavior by directly modulating the expression of BRCA1. Indeed, ectopic expression of wild-type BRCA1 phenocopied the tumor suppressor function of HOXA9, and reducing BRCA1 levels or function inhibited the antitumor activity ...
Breast cancer 1, early onset (BRCA1) expression is often reduced in sporadic breast tumors, even in the absence of BRCA1 genetic modifications, but the molecular basis for this is unknown. In this study, we identified homeobox A9 (HOXA9) as a gene frequently downregulated in human breast cancers and tumor cell lines and noted that reduced HOXA9 transcript levels associated with tumor aggression, metastasis, and patient mortality. Experiments revealed that loss of HOXA9 promoted mammary epithelial cell growth and survival and perturbed tissue morphogenesis. Restoring HOXA9 expression repressed growth and survival and inhibited the malignant phenotype of breast cancer cells in culture and in a xenograft mouse model. Molecular studies showed that HOXA9 restricted breast tumor behavior by directly modulating the expression of BRCA1. Indeed, ectopic expression of wild-type BRCA1 phenocopied the tumor suppressor function of HOXA9, and reducing BRCA1 levels or function inhibited the antitumor activity ...
Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04
We have characterized expression of the familial breast and ovarian cancer gene, BRCA1, in cases of non-hereditary (sporadic) breast cancer and analyzed the effect of antisense inhibition of BRCA1 on the proliferative rate of mammary epithelial cells. BRCA1 mRNA levels are markedly decreased during the transition from carcinoma in situ to invasive cancer. Experimental inhibition of BRCA1 expression with antisense oligonucleotides produced accelerated growth of normal and malignant mammary cells, but had no effect on non-mammary epithelial cells. These studies suggest that BRCA1 may normally serve as a negative regulator of mammary epithelial cell growth whose function is compromised in breast cancer either by direct mutation or alterations in gene expression ...
The BRCA1 and BRCA2 genes are the two major high-risk breast and/or ovarian cancer susceptibility genes. Monoallelic germline mutations that disrupt their normal gene function significantly increase the risk of developing cancer in carriers. The identification of a causal mutation in a proband allows proposing pre-symptomatic testing for the causal mutation to all at-risk relatives. Currently, a causal mutation, used for genetic counseling, is presented in approximatively 13% of families tested. Variants of unknown biological significance (VUS) are detected in more than 20% of proband tested. For the families of these probands, genetic testing could not be proposed to relatives and the genetic counseling is guided by family history and epidemiological knowledges exclusively.. The French UMD-BRCA1/2 database, accredited by the French National Cancer Institute, collects anonymous results of genetic tests performed by authorized French laboratories since 1995, giving a real-time vision of families ...
Estrogênio é essencial para a modulação da expressão do BRCA1. O gene BRCA1 apresenta na sua região promotora dois sítios de início de transcrição distintos, um localizado no éxon-1A e o outro no éxon-1B. O estrogênio é capaz de recrutar proteínas AP1 e o complexo receptor de estrogênio α /p300 a um sítio AP 1 adjacente ao sítio de início de transcrição do éxon 1B e de recrutar proteínas Sp (Sp1 e Sp4) há regiões próximas do sítio Ap1. Quando ocorre a ligação do estrogênio ao complexo receptor de estrogênio α /p300 há um desencadeamento de eventos de fosforilação que culminam na fosforilação do próprio complexo e de proteínas Sp que modulam a interação proteína-proteína do promotor do gene BRCA1.[16] O AhR (Aromatic hydrocarbon Receptor) é um outro importante receptor nuclear que atua na regulação da expressão de BRCA1 através de ligação direta em sua região promotora ou de forma indireta por intermédio de receptor estrogênio. Foi proposto ...
The tumor suppressor BRCA1 regulates the DNA damage response (DDR) and other processes that remain incompletely defined. Among these, BRCA1 heterodimerizes with BARD1 to ubiquitylate targets via its N-terminal E3 ligase activity. Here, it is demonstrated that BRCA1 promotes oxidative metabolism by degrading Oct1 (POU2F1), a transcription factor with proglycolytic and tumorigenic effects. BRCA1 E3 ubiquitin ligase mutation skews cells toward a glycolytic metabolic profile while elevating Oct1 protein. CRISPR-mediated Oct1 deletion reverts the glycolytic phenotype. RNA sequencing (RNAseq) confirms deregulation of metabolic genes downstream of Oct1. BRCA1 mediates Oct1 ubiquitylation and degradation, and mutation of two ubiquitylated Oct1 lysines insulates the protein against BRCA1-mediated destabilization. Oct1 deletion in MCF-7 breast cancer cells does not perturb growth in standard culture, but inhibits growth in soft agar and xenograft assays. In primary breast cancer clinical specimens, Oct1 ...
The novel zinc finger protein 121 (ZNF121) has been demonstrated to physically and functionally associate with the MYC oncoprotein to regulate cell proliferation and likely breast cancer development. To further understand how ZNF121 functions in cell proliferation and carcinogenesis, we identified and characterized the interaction of ZNF121 with zinc finger and BRCA1-interacting protein with a KRAB domain 1 (ZBRK1), a breast and ovarian cancer susceptibility protein 1 (BRCA1)-interacting protein, using the yeast two-hybrid assay and other approaches. We also found that ZNF121 bound to BRCA1. Functionally, ZFN121 suppressed the expression of ANG1 and HMGA2, two common downstream targets of ZBRK1 and BRCA1. Interestingly, ZNF121 also regulated the expression of BRCA1 and ZBRK1. These findings suggest that ZNF121 is likely a member of the BRCA1/CtIP/ZBRK1 repressor complex that plays a role in breast cancer ...
The novel zinc finger protein 121 (ZNF121) has been demonstrated to physically and functionally associate with the MYC oncoprotein to regulate cell proliferation and likely breast cancer development. To further understand how ZNF121 functions in cell proliferation and carcinogenesis, we identified and characterized the interaction of ZNF121 with zinc finger and BRCA1-interacting protein with a KRAB domain 1 (ZBRK1), a breast and ovarian cancer susceptibility protein 1 (BRCA1)-interacting protein, using the yeast two-hybrid assay and other approaches. We also found that ZNF121 bound to BRCA1. Functionally, ZFN121 suppressed the expression of ANG1 and HMGA2, two common downstream targets of ZBRK1 and BRCA1. Interestingly, ZNF121 also regulated the expression of BRCA1 and ZBRK1. These findings suggest that ZNF121 is likely a member of the BRCA1/CtIP/ZBRK1 repressor complex that plays a role in breast cancer ...
During the submission of this work, a study with consistent findings was published online (27). Both studies find that the coiled-coil domain present at the NH2 terminus of PALB2 directly binds to BRCA1 and that this interaction is required for the assembly of BRCA2 foci. In contrast to the other paper, however, we define and characterize two point mutants of the coiled-coil domain that disrupt binding to BRCA1. In this manner, we more specifically implicate PALB2 as a linker of BRCA1 and BRCA2. Furthermore, we directly compare PALB2-deficient cells reconstituted with mutants defective for interaction with either BRCA1 or BRCA2. This has led to a more definitive demonstration that PALB2 links BRCA1, BRCA2, and RAD51 into a DNA damage response pathway. Additionally, using the set of reconstituted cells, we have determined that PALB2 is positioned between BRCA1 and BRCA2 in this pathway. Unlike the other article, we assay the assembly of RAD51 foci and resistance to the DNA interstrand ...
BRCA1 / RNF53, 50 µg. BRCA1 (breast and ovarian cancer susceptibility protein 1) is a RING finger protein containing a BRCT domain.
BRCA1 / RNF53, 50 µg. BRCA1 (breast and ovarian cancer susceptibility protein 1) is a RING finger protein containing a BRCT domain.
New research is showing a link between the BRCA1 gene (the "breast cancer" gene) and infertility. An article published by http://www.medicaldaily.com reports researchers from a NIH funded institute found that the BRCA1 gene, in its functional form, aided in the repair of female egg cells, keeping them from self-destruction.. As female eggs age, DNA damage occurs. The body has mechanisms to help repair these eggs, but eventually those mechanisms wear out as we age, and our eggs are no longer able to be repaired and they self-destruct. Enter menopause. However, for some women menopause occurs much earlier than anticipated and/or they are told they have relatively low egg reserve at a very young age. What causes this to occur?. Researchers looked at the role the BRCA1 gene plays in DNA repair for eggs of lab mice. In this study researchers turned off the genes, including the BRCA1 gene, associated with repairing damaged egg cells:. ...
The BRCA gene encodes for the BRCA proteins, BRCA1 and BRCA2. These proteins are very important in repairing DNA, which they do by correcting double-stranded breaks.
Next, we investigated the binding domains of BRCA1 with AKT using an in vitro binding assay. A series of four overlapping GST fusion proteins, spanning the entire coding region of BRCA1, were used to define regions of BRCA1 that interact with AKT. Purified GST-BRCA1 fusion proteins were added to MCF7 cell-free extracts, and GST-BRCA1-AKT complexes were isolated with glutathione beads. pAKT, but not unphosphorylated AKT, was found to bind fragment 1501-1861 of BRCA1 as detected by Western blotting ( Fig. 2C). BRCA1 fragment 1501-1861 contains the BRCT domains, which are phospho-protein binding domains that are important for the tumor suppressor function of BRCA1. The recombinant BRCA1-BRCT domain (residues 1599-1863) fused to GST-bound endogenous pAKT from a MCF7 cell lysate ( Fig. 2D). The cancer-associated missense mutations M1775R and P1749R in the BRCT domains of the COOH terminus of BRCA1 ablate the functions of BRCA1 ( 2). We tested the binding ability of these BRCA1 mutants to pAKT and ...
This year approximately 243,000 women will be diagnosed with breast or ovarian cancer in the United States. One in eight women will develop breast cancer in her lifetime. A genetic predisposition is suspected in up to 15% of women who develop these disease and have one or more affected close relatives. Many of these families will be found to carry mutations in the two most well-known genes responsible for hereditary breast and ovarian cancer, the BRCA1 and BRCA2 genes. However, a significant portion of families that are suggestive of a genetic predisposition are found to not be linked to the BRCA1 and BRCA2 genes. What other genetic factors can explain the risk in such families? How can we improve our ability to predict breast cancer risk for future generations? Help us to find out and be a part of the solution. For more detailed information about the study, go to our study page. Click here for our study card to share with your friends and family members. ...
To further explore whether BRCA1 enrichment and its associated exclusion of 53BP1 from the IRIF core correlates with inhibition of 53BP1-dependent repair at DSB sites during S phase, we analysed cells recovering from acute treatment with camptothecin (CPT), a topoisomerase I inhibitor that induces DSBs in S phase when replication forks encounter trapped Top1-DNA cleavage complexes (Pommier et al., 2003). In BRCA1-deficient cells, CPT-induced chromosomal aberrations are 53BP1 dependent; indicating BRCA1 normally counteracts 53BP1-mediated repair activities in this context (Bunting et al., 2010). Consistent with this notion, CPT-induced foci closely resembled S-phase IRIF by 3D-SIM, with BRCA1 and 53BP1 adopting equivalent focal positions (Fig. 4C). The repair of DSBs by HR in S phase also relies on CtIP-mediated DNA-end resection (Sartori et al., 2007). Consistent with a model in which the focus core corresponds to sites of HR in S-phase cells, 3D-SIM analysis of CtIP localisation in irradiated ...
Patients with GBM tumors expressing low levels of BRCA1 were demonstrated to be associated with prolonged survival when compared with GBM patients with tumors expressing higher levels of the proteins - median overall survival was found to be 18.9 vs 4.8 months, respectively.. Archived tissue microarrays of tumor samples isolated from 66 GBM patients who had participated in Radiation Therapy Oncology Group clinical trials underwent analysis for RAD51, BRCA1, PTEN, and miRNA-210 protein expression. These 66 patients had all been treated with surgery, radiotherapy and non-temozolomide chemotherapy, and had a similar overall survival.. "BRCA1 is a tumor suppressor gene that is involved in DNA repair. Mutations of this gene, or deficient protein due to epigenetic changes, lead to DNA damage repair failure," explained the studys principal investigator Maria Vasilakopoulou (Pitié-Salpêtrière Hospital, Paris, France). "The study results suggest strongly that low BRCA1 protein expression in the GBM ...
INTRODUCTION: Preservation of structure and function of the myocardium is critically dependent upon improving the survival of existing cardiomyocytes (CM), through strategies that limit CM apoptosis and DNA damage. BRCA1 is a tumor suppressor gene which functions to promote DNA repair, and protect cells against oxidative and genotoxic stress. We hypothesized that BRCA1 is a novel cellular target to limit CM apoptosis, and prevent aberrant cardiac remodeling.. METHODS AND RESULTS: Experimental MI in mice caused a profound 16-fold upregulation in BRCA1 expression, which peaked at 72 hours (p,0.01). In vitro gain-of-function experiments demonstrated that Ad-BRCA1 overexpression protected neonatal rat CM against doxorubicin- and H2O2-induced apoptosis, as assessed by FACS (p,0.01) and activated caspase-3. Ad-BRCA1-expressing CM exhibited a profound reduction in p53 expression in response to doxorubicin and H2O2. Co-immunoprecipitation studies demonstrated a distinct physical interaction of BRCA1 ...
What are BRCA1 and BRCA2? BRCA1 and BRCA2 are human genes that produce tumor suppressor proteins. These proteins help repair damaged DNA and, therefore, play a role in ensuring the stability of the cells genetic material. When either of these genes is mutated, or altered, such that its protein product either is not made or…
TY - JOUR. T1 - HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype. AU - Gilbert, Penney M.. AU - Mouw, Janna K.. AU - Unger, Meredith A.. AU - Lakins, Johnathon N.. AU - Gbegnon, Mawuse K.. AU - Clemmer, Virginia B.. AU - Benezra, Miriam. AU - Licht, Jonathan D.. AU - Boudreau, Nancy J.. AU - Tsai, Kelvin K.C.. AU - Welm, Alana L.. AU - Feldman, Michael D.. AU - Weber, Barbara L.. AU - Weaver, Valerie M.. PY - 2010/5/3. Y1 - 2010/5/3. N2 - Breast cancer 1, early onset (BRCA1) expression is often reduced in sporadic breast tumors, even in the absence of BRCA1 genetic modifications, but the molecular basis for this is unknown. In this study, we identified homeobox A9 (HOXA9) as a gene frequently downregulated in human breast cancers and tumor cell lines and noted that reduced HOXA9 transcript levels associated with tumor aggression, metastasis, and patient mortality. Experiments revealed that loss of HOXA9 promoted mammary epithelial cell growth and survival and perturbed ...
Ali, A.B., Iau, P.T.C., Sng, J.-H. (2010). Cancer-specific methylation in the BRCA1 promoter in sporadic breast tumours. Medical Oncology 28 (1) : 64-66. [email protected] Repository. https://doi.org/10.1007/s12032-010-9438- ...
Purpose: Breast cancers in carriers of inactivating mutations of the BRCA1 gene carry a specific DNA copy-number signature ("BRCA1-like"). This signature is shared with cancers that inactivate BRCA1 through other mechanisms. Because BRCA1 is important in repair of DNA double-strand breaks through error-free homologous recombination, patients with a BRCA1-like tumor may benefit from high-dose alkylating (HD) chemotherapy, which induces DNA double-strand breaks.. Experimental Design: We investigated a single institution cohort of high-risk patients that received tandem HD chemotherapy schedule comprising ifosfamide, epirubicin, and carboplatin or conventional chemotherapy. We classified copy-number profiles to be BRCA1-like or non-BRCA1-like and analyzed clinical associations and performed survival analysis with a treatment by biomarker interaction design.. Results: BRCA1-like status associated with high-grade and triple-negative breast cancers. BRCA1-like cases benefitted from the HD compared ...
A pair of studies could change the way patients are evaluated for mutations of BRCA1 and BRCA2, two cancer susceptibility genes closely associated with breast and ovarian cancers, as well as other tumor types.