Premature senescence is a major response to DNA cross-linking agents in BRCA1-defective cells: implication for tailored treatments of BRCA1 mutation carriers.
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.
Experimental Oncology 1, Centro di Riferimento Oncologico, Istituto Di Ricovero e Cura a Carattere Scientifico, National Cancer Institute, via F. Gallini 2, Aviano 33081 PN, Italy.
Manuela
M
Santarosa
Laura
L
Del Col
Elena
E
Tonin
Angela
A
Caragnano
Alessandra
A
Viel
Roberta
R
Maestro
D019588:Aging, Premature / Q000503:physiopathology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D002461:Cell Line, Transformed / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D003114:Colony-Forming Units Assay; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D019313:BRCA1 Protein; D003432:Cross-Linking Reagents; D016685:Mitomycin; D005047:Etoposide; D004317:Doxorubicin; D002945:Cisplatin