Premature senescence is a major response to DNA cross-linking agents in BRCA1-defective cells: implication for tailored treatments of BRCA1 mutation carriers

Abstract

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 β-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.

Biology and Management of Patients With Triple-Negative Breast Cancer

“…Repair of platinum-induced interstrand crosslinks invokes BRCA1-mediated homologous recombination (HR), and there is abundant clinical and in vitro evidence that BRCA1-deficient cells are hypersensitive to platinum agents [61][62][63]. Observational, small neoadjuvant, and metastatic studies have demonstrated that BRCA mutation-associated breast cancers are sensitive to platinum agents [61,[63][64][65][66][67].…”

Are there roles for brain cell senescence in aging and neurodegenerative disorders?

“…mRNA and miRNA expression profiles of different human tissues during aging reveal the existence of a common pattern of defined transcriptional and epigenetic changes as well as tissue-specific age-related alterations (ElSharawy et al, 2012; Li et al, 2009; Maes et al, 2009; Ren et al, 2012; Santarosa et al, 2009; Serna et al, 2012). …”

BRCA1 and Oxidative Stress

“…On the other hand, increasing cellular ROS production may be utilized to treat BRCA1-associated cancers. Indeed, BRCA1 mutated cancers are particularly sensitive to genotoxic and oxidative agents including PARP inhibitors and chemotherapeutics [198,199,200,201]. Thus, specific targeting of oxidative stress in BRCA1-defective tumors may provide alternative treatment options [202,203].…”