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BRCA1

breast cancer 1, early onset;BRCA1;breast cancer 1, early onset

BRCA1/BRCA2-containing complex, subunit 1|Fanconi anemia, complementation group S|RING finger protein 53|breast and ovarian cancer susceptibility protein 1|breast and ovarian cancer sususceptibility protein 1|breast cancer type 1 susceptibility protein|pr

17q21

protein-coding

BRCA1-associated tumors are characterized by an elevated genomic instability and peculiar expression profiles. Nevertheless, tailored treatments for BRCA1 mutation carriers have only been partially investigated up to now. The implementation of therapeutic strategies specific for these patients has been in part hindered by the paucity of proper preneoplastic and neoplastic BRCA1-deficient tumor cell models. In this study, we took advantage of the RNA interference technology to generate a series of partially transformed (HBL100) and tumorigenic (MCF7 and T47D) breast cancer cell lines in which BRCA1 expression was silenced at different levels. These cell models were probed by clonogenic assay for their response to several DNA-damaging agents commonly used in cancer therapy (mitomycin C, cisplatin, doxorubicin, and etoposide). Our models confirmed the peculiar sensitivity to interstrand cross-link inducers associated with BRCA1 deficiency. Intriguingly, the increased sensitivity to these compounds displayed by BRCA1-defective cells was not correlated with the extent of apoptotic cell death but rather associated to an increased fraction of growth-arrested, enlarged, multinucleated beta-galactosidase-positive senescent cells. Overall, our results support a role for BRCA1 in the regulation of interstrand cross-link-induced premature senescence and suggest a reconsideration of the therapeutic power of mitomycin/platinum-based treatments in BRCA1 carriers. Moreover, our data further prompt the setup of strategies for the imaging of the senescence response in vivo.

Resveratrol decreases cancer risk and improves health of laboratory animals. However, it can also promote genomic instability. Part of the beneficial activity of resveratrol may result from the activation of SIRT1 deacetylase. We examined how resveratrol influenced the growth of human cancer cell lines of different origin: osteosarcoma (U-2 OS) and lung adenocarcinoma (A549) and how it modulated the expression as well as the localization of key proteins, involved in DNA repair and cell cycle regulation. Resveratrol-induced growth arrest was associated with signs of stress-induced senescence. Differential expression of BRCA1, cyclin B1, pRb and p21 in U-2 OS and A549 cells indicates that resveratrol can engage various molecular mechanisms to arrest cell cycle progression. In subset of U-2 OS cells, the upregulated BRCA1 formed foci closely associated with WRN and the telomeric protein (TRF1). Moreover, resveratrol induced telomeric instability in U-2 OS cells and the activation of DNA damage signaling in both cell lines, manifested as the phosphorylation of histone H2AX at serine 139 and of p53 at serines 15 and 37. Our data are consistent with the hypothesis that resveratrol inhibits cell growth and induces senescence by altering DNA metabolism.

The definition of an oncogene is a gene that actively promotes tumorigenesis. For example, activation of RAS oncogene promotes cell transformation and cancer. Paradoxically, in primary mammalian cells, oncogenic RAS typically triggers cellular senescence, a state of irreversible cell growth arrest. Oncogene-induced senescence is an important tumor suppression mechanism in vivo. Here, we discuss our recent evidence that RAS-induced suppression of DNA repair response via dissociation of BRCA1 from chromatin promotes senescence while predisposing cells to senescence bypass and transformation by allowing for secondary hits. The molecular mechanism we uncovered helps reconcile the tumor-promoting nature of oncogenic RAS with the tumor-suppressing role of oncogene-induced senescence.