Differential sensitivity of BRCA1-mutated HCC1937 human breast cancer cells to microtubule-interfering agents

Abstract

Germ-line mutations in the breast cancer susceptibility BRCA1 gene account for approximately half of hereditary breast cancer cases and most of breast/ovarian cancer cases. We speculated whether breast hereditary cancers might be differentially sensitive to antitumor agents such as the mitotic spindle poisons Vinca alcaloid vinorelbine (VNR) and the taxoid docetaxel (DOC), which are commonly used in the treatment of breast cancer. We investigated the sensitivity of the BRCA1-mutated HCC1937 (derived from a BRCA1 related hereditary tumor) and BRCA1 competent MCF-7 and MDA-MB468 sporadic breast cancer cell lines to these drugs. We found that HCC1937 cells were significantly more sensitive to VNR as compared to MCF-7 or MDA-MB468 cells. Instead, BRCA1-mutated breast cancer cells exposed to DOC showed similar sensitivity as compared to BRCA1-competent MCF-7 or were less sensitive than MDA-MB468. In order to assess the role of BRCA1 in this specific pattern of chemosensitivity, we transfected the BRCA1-mutated HCC1937 cells with a full-length BRCA1 cDNA and the stable clone (HCC1937/WTBRCA1) was exposed to both drugs. Full-length BRCA1 transfection led to a significant induction of resistance to VNR, whereas only a weak but not significant increase of sensitivity to DOC was detected. Moreover, VNR induced apoptotic cell death and cytoskeletal rearrangements in HCC1937 cells. We further investigated whether a defective targeting of mitotic spindle by the mutated BRCA1 gene product might be involved in the differential sensitivity to VNR. We demonstrated that mutated BRCA1 was indeed capable of co-localizing with alpha-tubulin in the mitotic spindle, suggesting therefore that different mechanisms should account for these effects. In conclusion, our data suggest that BRCA1-mutated tumors might be differentially sensitive to anti-microtubule agents, supporting the rationale for clinical trials to improve the outcome of hereditary breast cancer patients by tailored treatments.