BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair.

Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Carcinogenesis (Impact Factor: 5.27). 06/2010; 31(6):961-7. DOI: 10.1093/carcin/bgq069
Source: PubMed

ABSTRACT BRCA1 and BRCA2 are tumor suppressor genes, familial mutations in which account for approximately 5% of breast cancer cases in the USA annually. Germ line mutations in BRCA1 that truncate or inactivate the protein lead to a cumulative risk of breast cancer, by age 70, of up to 80%, whereas the risk of ovarian cancer is 30-40%. For germ line BRCA2 mutations, the breast cancer cumulative risk approaches 50%, whereas for ovarian cancers, it is between 10 and 15%. Both BRCA1 and BRCA2 are involved in maintaining genome integrity at least in part by engaging in DNA repair, cell cycle checkpoint control and even the regulation of key mitotic or cell division steps. Unsurprisingly, the complete loss of function of either protein leads to a dramatic increase in genomic instability. How they function in maintaining genome integrity after the onset of DNA damage will be the focus of this review.

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    ABSTRACT: Genomic instability finally induces cell death or apoptosis. The tumor suppressor, phosphatase and tensin homolog on chromosome 10 (PTEN), is a dual-specificity phosphatase, which has protein phosphatase activity and lipid phosphatase activity that antagonizes PI3K activity. Cells that lack PTEN have constitutively higher levels of PIP3 and activated downstream PI3K/AKT targets. BRCA1, a well-known breast cancer tumor suppressor, is to associate with breast cancer risk and genetic susceptibility. Many studies have demonstrated that PTEN, as well as BRCA1, plays a critical role in DNA damage responses. The BRCA1 functionally cooperates with PTEN and might be an essential blockage in the development of several tumors. Actually, the PTEN and BRCA1 genes are recognized as one of the most frequently deleted and/or mutated in many human cancers. The PI3K/AKT pathway is constitutively active in BRCA1-defective human cancer cells. Loss or decrease of these PTEN or BRCA1 function, by either mutation or reduced expression, has a role in various tumor developments. This review summarizes recent findings of the function of BRCA1 and PTEN involved in genomic stability and cancer cell signaling.
    Frontiers in Oncology 11/2014; 4:318. DOI:10.3389/fonc.2014.00318
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    ABSTRACT: Sister chromatid exchange (SCE) frequency is widely used as an indicator of spontaneous chromosome instability. We investigated SCE frequency in the peripheral blood lymphocytes of familial and sporadic breast cancer (BC) patients from the Apulian Caucasian Population. Eighty-one patients were enrolled: 22 with familial history and 59 sporadic patients. Eleven familial patients had an 'increased risk' of BRCA gene mutation (BRCAPro ≥10%) and were candidates for BRCA1 and BRCA2 mutation analysis. For these reasons, we stratified the 22 familial BC patients in two group: 'low-risk' (n=11) and 'high-risk' (n=11) patients for BRCA gene mutations. Two of these 11 'high-risk' patients (18%) had pathogenic mutations in the BRCA2 gene. The subjects were not cigarette smokers or alcohol or drug users, and had no genetic disorders or chronic diseases affecting the family. Our results showed a significant increase in SCE frequency in the familial (5.305±1.088/metaphase) (P<0.0001) and the sporadic patients (3.943±0.552) (P<0.0001) compared to the controls (3.197±0.649). We found that the SCE frequency was always significantly higher in familial than in sporadic patients, regardless of their clinicopathological characteristics. Moreover, we observed that the frequency of SCE in BRCA2 mutation carrier patients was higher compared to patients without mutations in BRCA1/2 genes. These findings highlight an intrinsic genomic instability in familial patients, and we suggest that SCE frequency may be used as a biomarker to better characterize familial BC.
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