*  NewYork-Presbyterian/Queens - Genetics and Cancer - Hereditary Breast Ovarian Cancer Syndrome (BRCA1 / BRCA2)
In 1990, DNA linkage studies on large families with the above characteristics identified the first gene associated with breast cancer. Scientists named this gene breast cancer 1, or BRCA1 (pronounced brak-uh). BRCA1 is located on chromosome 17. Mutations in the gene are transmitted in an autosomal dominant pattern in a family.. Since it was clear that not all breast cancer families were linked to BRCA1, studies continued and in 1994, scientists discovered another gene (similar to BRCA1) and named it BRCA2. BRCA2 is located on chromosome 13. Mutations in this gene are also transmitted in an autosomal dominant pattern in a family.. Both BRCA1 and BRCA2 are tumor suppressor genes that usually have the job of controlling cell growth and cell death. Everyone has two ...
  http://www.nyhq.org/diw/Content.asp?PageID=DIW007227
*  HUWE1 interacts with BRCA1 and promotes its degradation in the ubiquitin-proteasome pathway (Biochemical and Biophysical...
Highlights: • The 2000-2634 aa region of HUWE1 mediates the interaction with BRCA1 degron. • HUWE1 promotes the degradation of BRCA1 through the ubiquitin-proteasome pathway. • HUWE1 expression is inversely correlated with BRCA1 in breast cancer cells. • RNAi inhibition of HUWE1 confers increased resistance of MCF-10F cells to IR and MMC. - Abstract: The cellular BRCA1 protein level is essential for its tumor suppression activity and is tightly regulated through multiple mechanisms including ubiquitn-proteasome system. E3 ligases are involved to promote BRCA1 for ubiquitination and degradation. Here, we identified HUWE1/Mule/ARF-BP1 as a novel BRCA1-interacting protein involved in the control of BRCA1 protein level. HUWE1binds BRCA1 through its N-terminus degron domain. Depletion of HUWE1 by siRNA-mediated interference ...
  https://www.osti.gov/scitech/biblio/22416269-huwe1-interacts-brca1-promotes-its-degradation-ubiquitinproteasome-pathway-biochemical-biophysical-research-communications-issue
*  Triple-negative breast cancer and PTEN (phosphatase and tensin homologue)loss are predictors of BRCA1 germline mutations in...
Our study in an Asian series of triple-negative breast cancer patients demonstrated that up to 24.5% (27 of 110) women have germline mutations in BRCA1 (23 of 110) and BRCA2 (four of 110), and that the addition of negative estrogen-receptor status and PTEN loss improves the sensitivity of the Manchester Scoring method in our Asian cohort.. The results in this study are consistent with that in other cohorts of triple-negative breast cancer patients, in whom 11% to 39% have germline mutations in BRCA1 and BRCA2 [3, 6, 20-23], and cohorts of estrogen-receptor-negative breast cancer patients, of whom 24% to 29% have germline mutations in BRCA1 and BRCA2 [4, 6, 24, 25]. A recent single-institution study showed that 50% of high-risk patients with TNBC had mutations in BRCA1/2, but notably, 76% of this cohort had a family history of breast cancer [10]. For all of these series and for our study, ...
  https://breast-cancer-research.biomedcentral.com/articles/10.1186/bcr3347
*  hCds1 phosphorylates BRCA1 after DNA damage | Breast Cancer Research | Full Text
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 ...
  https://breast-cancer-research.biomedcentral.com/articles/10.1186/bcr-2000-66667
*  Long-term prospective clinical follow-up after BRCA1/2 presymptomatic testing: BRCA2 risks higher than in adjusted...
Results Nineteen breast cancers occurred in women undergoing presymptomatic testing for BRCA1 and 23 for BRCA2. Breast cancer incidence for BRCA2 was marginally higher than BRCA1 at 20.05 per 1000 in BRCA2 compared with 16.20 per 1000 in BRCA1. Penetrance estimates to 70 years of age adjusted for a 6-month lead time and oophorectomy using Kaplan-Meier analysis were 55.1% (95% CI 36.5% to 75.6%) for BRCA1 and 71.5% (95% CI 53.2% to 87.6%). Breast cancer cases were associated with stronger family histories and higher SNP aggregate scores in BRCA2.. ...
  http://jmg.bmj.com/content/early/2014/07/22/jmedgenet-2014-102336
*  Rotating night work, lifestyle factors, obesity and promoter methylation in BRCA1 and BRCA2 genes among nurses and midwives. -...
Some recent evidence suggests that environmental and lifestyle factors may modify DNA methylation. We hypothesized that rotating night work and several modifiable factors may be associated with the methylation of the promoter regions within two tumor suppressor and DNA repair genes: BRCA1 and BRCA2. The methylation status of BRCA1 and BRCA2 was determined via qMSP reactions using DNA samples derived from blood leucocytes of 347 nurses and midwives working rotating nights and 363 working during the days. The subjects were classified into unmethylated vs methylated BRCA1 and BRCA2 when the methylation index was 0% or ,0%, respectively. The adjusted odds ratios with 95% confidence intervals were calculated for night work status, smoking, obesity, physical activity and alcohol drinking. Current night shift work or night work history was not associated with methylation status of the promoter ...
  http://ecnis.openrepository.com/ecnis/handle/10146/618141
*  "The Role of BRCT-Containing Proteins BRCA1 and PAXIP1 in Cancer" by Ankita Jhuraney
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 ...
  http://scholarcommons.usf.edu/etd/5819/
*  Plus it
4995 Fanconi anemia (FA) is a cancer-susceptibility syndrome characterized by hypersensitivity to DNA crosslinking agents, such as cisplatin and mitomycin C. All 9 known FA proteins cooperate with breast/ovarian cancer susceptibility gene products (BRCA1 and BRCA2) in a common DNA damage-activated signaling pathway called the Fanconi anemia(FA)-BRCA pathway. Seven FA proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCL) are components of a multi-subunit ubiquitin ligase complex (FA complex) required for monoubiquitination of FANCD2. After DNA damage, FANCD2 is monoubiquitinated and targeted to BRCA1/BRCA2-containing nuclear foci in an ATR kinase-dependent fashion. Importantly, the pathway is inactivated in a wide variety of human cancers by methylation of the FANCF gene. This inactivation causes cisplatin sensitivity in some ovarian cancer cell ...
  http://cancerres.aacrjournals.org/content/65/9_Supplement/1180.1
*  Evidence that the tumor-suppressor protein BRCA2 does not regulate cytokinesis in human cells | Journal of Cell Science
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. ...
  http://jcs.biologists.org/content/early/2010/03/31/jcs.068015
*  Cancers | Free Full-Text | BRCA1 and Oxidative Stress
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 BRCA1's 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.
  http://www.mdpi.com/2072-6694/6/2/771
*  Cancers | Free Full-Text | BRCA1 and Oxidative Stress | HTML
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 BRCA1's 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.
  http://www.mdpi.com/2072-6694/6/2/771/htm
*  Cancer and The BRCA1 and BRCA2 Gene - The Fight For Our Bodies
A woman's 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 ...
  http://ignoremelikeyoumeanit.blogspot.com/2009/05/cancer-and-brca1-and-brca2-gene-fight.html
*  Handbook of Genetic Counseling/Retinoblastoma - Wikibooks, open books for an open world
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 ...
  https://en.wikibooks.org/wiki/Handbook_of_Genetic_Counseling/Retinoblastoma
*  BRCA1 mutations in primary breast and ovarian carcinomas
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 ...
  http://www.meb.uni-bonn.de/cgi-bin/mycite?ExtRef=MEDL/95025878/PMID/7939630
*  HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype. | Center for Bioengineering & Tissue Regeneration
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 ...
  http://weaverlab.ucsf.edu/content/hoxa9-regulates-brca1-expression-modulate-human-breast-tumor-phenotype?page=3
*  HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype. | Center for Bioengineering & Tissue Regeneration
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 ...
  http://weaverlab.ucsf.edu/content/hoxa9-regulates-brca1-expression-modulate-human-breast-tumor-phenotype?page=4
*  HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype. | Center for Bioengineering & Tissue Regeneration
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 ...
  http://weaverlab.ucsf.edu/content/hoxa9-regulates-brca1-expression-modulate-human-breast-tumor-phenotype?page=5
*  HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype. | Center for Bioengineering & Tissue Regeneration
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 ...
  http://weaverlab.ucsf.edu/content/hoxa9-regulates-brca1-expression-modulate-human-breast-tumor-phenotype?page=6
*  HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype. | Center for Bioengineering & Tissue Regeneration
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 ...
  http://weaverlab.ucsf.edu/content/hoxa9-regulates-brca1-expression-modulate-human-breast-tumor-phenotype?page=7
*  HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype. | Center for Bioengineering & Tissue Regeneration
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 ...
  http://weaverlab.ucsf.edu/content/hoxa9-regulates-brca1-expression-modulate-human-breast-tumor-phenotype?page=8
*  HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype. | Center for Bioengineering & Tissue Regeneration
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 ...
  http://weaverlab.ucsf.edu/content/hoxa9-regulates-brca1-expression-modulate-human-breast-tumor-phenotype?page=9
*  BRCA1 Antibodies - Molecular Mechanisms of Cancer | Sigma-Aldrich
The nuclear phosphoprotein encoded by BRCA1 functions as a tumor suppressor via a large multi-subunit protein complex, the BRCA1-associated genome surveillance complex (BASC), which contains other tumor suppressor proteins, DNA damage sensors and signal transducer proteins and participates in maintenance of genomic stability. Other functions ascribed to BRCA1 include double strand DNA break repair, chromatin remodeling and transcriptional regulation and links to cell cycle checkpoint regulation and induction of apoptosis. Loss of BRCA1 function leads to spontaneous chromosome breakage, and mutations in BRCA1 and BRCA2, another tumor suppressor and DNA repair mediating protein, are present in up to 80% of inherited breast and ovarian cancers. Functional characterization of these proteins in normal breast ...
  http://www.sigmaaldrich.com/life-science/cell-biology/antibodies/antibody-products.html?TablePage=111720510
*  BRCA1 Gene Mutation Associated with Neoadjuvant Chemotherapy | MD Anderson Cancer Center
Nearly half of breast cancer patients carrying the BRCA1 gene mutation experience a complete pathological response(pCR) - the disappearance of all evidence of disease from the breast tissue and lymph nodes - regardless of disease stage after standard neoadjuvant chemotherapy, according to new research from The University of Texas MD Anderson Cancer Center.. The study, published online in The Journal of Clinical Oncology on September 6, is the largest study to date to find that the pCR rate is significantly higher in BRCA1 carriers (46 percent) than in women carrying the BRCA2 mutation (13 percent) and non-carriers (22 percent). Among all the women, researchers did not find a statistical difference in overall survival rates, but noted that BRCA1 carriers who achieved a pCR had better five-year, relapse-free survival and overall survival rates.. BRCA1 and BRCA2 belong to a class of human ...
  https://www.mdanderson.org/newsroom/2011/09/brca1-gene-mutation-associated-with-neoadjuvant-chemotherapy.html
*  Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression
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 ...
  http://www.meb.uni-bonn.de/cgi-bin/mycite?ExtRef=MEDL/95315998/PMID/7795653
*  COsegregation of VARiants in the BRCA1/2 Genes - Full Text View - ClinicalTrials.gov
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 ...
  https://clinicaltrials.gov/ct2/show/NCT01689584?recr=Open&intr=%22Genetic+Counseling%22&rank=11