Together, our findings identify deubiquitination as a means to regulate BRCA2 function and point to USP21 as a potential therapeutic target in BRCA2-proficient tumors.BRCA2 is essential for the repair of DNA damage; therefore, defects in BRCA2 are associated with tumorigenesis but also with increased susceptibility to genotoxic stress.
Hypermethylation of DR5 (P=0.001), DCR1 (P=0.00001), DCR2 (P=0.0000000005) and BRCA2 (P=0.007) and hypomethylation of DR4 (P=0.011) in sporadic breast tumor tissues suggested a weak/aberrant activation of the DDR/apoptotic pathway in breast tumorigenesis.
BRCA1 and BRCA2 genes are critical in homologous recombination DNA repair and have been implicated in familial breast and ovarian cancer tumorigenesis.
Loss of such control in response to estrogen-induced DNA damage after BRCA2 inactivation may be a key initial event triggering genome instability and carcinogenesis.
Perhaps conflicting with common suspicions, the data are not compatible with selective pressures during tumorigenesis promoting the functional loss of BRCA2 and MRE11 in MSI tumors.
Thus, BRCA2 mutations probably contribute to gastrointestinal tumorigenesis other then colon cancer, and the surveillance scheme for mutation carriers should incorporate this information.
These findings suggest a model wherein carcinogenesis in BRCA2 mutation carriers can be incited by compounds found pervasively in the environment and generated endogenously in certain tissues with implications for public health.
BRCA1 and BRCA2, show defects in DNA repair by homologous recombination, implicating this repair pathway in protecting individuals against tumorigenesis.
Our results were consistent with the hypothesis that BRCA1 and BRCA2 mutations have a limited role in sporadic ovarian carcinogenesis in the Korean population.
These studies not only surprisingly show that BRCA2 does not follow the classical Knudson "two hit" paradigm for tumour suppression, but also highlight features of the interplay between TP53 inactivation and carcinogenesis in the context of BRCA2 deficiency.
Carriers of one mutant allele of either BRCA1 or BRCA2 are at risk for somatic loss of the second wild-type allele, leading to the initiation of breast tumorigenesis.
This study reveals an elaborate but highly organized molecular interplay between Rad51 regulators and has significant implications for understanding tumorigenesis and therapeutic resistance in patients with BRCA2 deficiency.
We show that the human tumor suppressor BRCA2 interacts with RNAPII to regulate PPP release, thereby preventing unscheduled RNA-DNA hybrids (R-loops) implicated in genomic instability and carcinogenesis.
BRCA2 has been found to be overexpressed in many breast tumors, suggesting that altered expression of the BRCA2 gene may contribute to breast tumorigenesis.
These data suggest that microsatellite instability and loss of unidentified genes on chromosome 8p may be involved in carcinogenesis of the prostate; however, BRCA1 and BRCA2 may not be largely involved in the development of prostate cancer in the Japanese population.
Although evidence that the hereditary breast cancer genes, BRCA1 and BRCA2, are involved in DNA repair suggests that genomic instability plays an important role in hereditary breast tumorigenesis, genomic instability remains poorly characterized in sporadic breast cancers.
The present study aimed to elucidate the expression profiles, mutations and interaction networks of BRCA1 and BRCA2, which may provide insights to reveal the mechanisms of BRCA genes ultimately leading to breast or ovarian tumorigenesis.
Mammary (and other) tumors occur at long latency as compared to oncogene-induced mouse tumors. p53 deficiency is highly cooperative with both Brca1 and Brca2 in promoting tumorigenesis.