BRCA1 suppresses the expression of survivin and promotes sensitivity to paclitaxel through the calcium sensing receptor (CaSR) in human breast cancer cells.

Both BRCA1 and CaSR have been shown to suppress the expression of survivin and promote sensitivity to paclitaxel in human breast cancer cells. In this study we determined the functional linkage, if any, between BRCA1 and CaSR. We found that mutant cells (harboring mutant BRCA1 with loss of BRCA1 expression) had a significant reduction in the expression of CaSR with a concurrent up-regulated expression of survivin and were resistant to paclitaxel by comparison to wild type cells (harboring wild type BRCA1 and expressing BRCA1). Knocking down the expression of BRCA1 in wild type cells resulted in a reduction in CaSR expression with a concurrent up-regulated expression of survivin and reduction in sensitivity to paclitaxel. Re-expression of BRCA1 in BRCA1 knocked-down wild type cells restored CaSR expression with a concurrent down-regulated expression of survivin and restoration of sensitivity to paclitaxel. Corollary, ectopic expression of BRCA1 in mutant cells induced CaSR expression, suppressed the expression of survivin and restored sensitivity to paclitaxel. These results suggest that BRCA1 action is linked to that of CaSR. In a final series of experiments, we show that ectopic expression of CaSR in either the BRCA1 knocked-down wild type or mutant cells suppressed the expression of survivin and promoted sensitivity to paclitaxel. Thus, CaSR can rescue BRCA1 defective cells from the deleterious effects of loss of BRCA1 function. CaSR expression, however, had no effect on the expression of BRCA1. BRCA1 could stimulate the transcriptional activities of the CaSR gene and shRNA targeting CaSR circumvented the action of BRCA1. We conclude, and report for the first time, that BRCA1 regulates the expression of CaSR and that it functions through CaSR in suppressing the expression of survivin and promoting sensitivity to paclitaxel.
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