CtlP (RBBP8) a Critical Player in the Development of Tamoxifen Resistance in Human Breast Cancer

摘要

Tamoxifen resistance constitutes a major clinical challenge in breast cancer therapy. However, the mechanisms involved are still poorly understood. Using serial analysis of gene expression (SAGE) based profiling of our recently developed tamoxifen resistant human breast cancer cell line, we identified CtIP, a BRCA1- and CtBP-interacting protein, as one of the most significantly down-regulated transcripts in tamoxifen resistant cells. This result was independently confirmed by quantitative real-time RT-PCR and Western blot analyses. Therefore, we hypothesized that down-regulation of CtIP constitutes a critical event for the development of tamoxifen resistance in breast cancer cells. Our results demonstrated that silencing CtIP by means of siRNA in tamoxifen sensitive cells confers tamoxifen resistance and estrogen independence in vitro, and reintroduction of CtIP into tamoxifen resistant cells restores sensitivity to the inhibitory growth effects of tamoxifen. Importantly, immunohistochemical studies of CtIP expression in primary breast carcinomas show that CtIP status strongly correlates with clinical response to endocrine therapy, and patients with progressive diseases have significantly lower CtIP levels than those who completely respond. These findings indicate that CtIP silencing may be a novel mechanism of the development of tamoxifen resistance in breast cancer cells and suggest that CtIP maybe a potential biomarker to predict clinical response to endocrine therapy. In addition, we also found that silenced expression of CtIP in tamoxifen resistant cells is not due to promoter CpG islands methylation, suggesting that other mechanisms, such as transcriptional repression, may be involved.