| Summary: | Endocrine agents have become the primary adjuvant treatment for breast cancer. In addition to endocrine therapy, cytotoxic chemotherapeutic agents have also been frequently used in the neoadjuvant and adjuvant settings, to reduce tumour size prior to surgery or to reduce the chance of relapse or metastasis. However, patients can be resistant to endocrine and chemotherapeutic agents, or become resistant after long term treatment. In this study, I investigated the role and the regulation of FOXM1 in the sensitivity and resistance to the endocrine agent, tamoxifen, and the cytotoxic chemotherapeutic agent, epirubicin. Firstly, I demonstrated that tamoxifen repressed FOXM1 expression in sensitive but not in tamoxifen resistant breast cancer cell lines. In MCF-7 cells, FOXM1 protein and mRNA expression levels were regulated by ER-ligands, and depletion of ERα by RNA interference down-regulated FOXM1 expression. Importantly, ectopic expression of FOXM1 abrogated the cell cycle arrest mediated by the anti-oestrogen tamoxifen, and conferred tamoxifen resistance to MCF-7 cells. In contrast, silencing of FOXM1 in tamoxifen resistant cells abolished oestrogen-induced MCF-7 cell proliferation and overcame acquired tamoxifen resistance. Secondly, FOXM1 expression analysis in epirubicin resistant MCF-7 cells showed a higher level compared with MCF-7 cells. In addition, epirubicin treatment down-regulated FOXM1 expression in MCF-7, but FOXM1 protein level remained constant in epirubicin resistant MCF-7 cells. I established that p53 repressed FOXM1 expression in MCF-7 cells, while this protein is lost in the MCF-7 epirubicin resistant cells. I also found that ataxia-telangiectasia mutated (ATM) was overexpressed at protein and mRNA levels in epirubicin resistant MCF-7 compared with MCF-7 cells, and that ATM depletion strongly decreased FOXM1 expression. Epirubicin treatment increased DNA damage levels in MCF-7 cells while this remained constant in similarly treated epirubicin resistant MCF-7 cells, suggesting a higher level of DNA repair in these cells. Taken together, these results indicate that deregulation of FOXM1 may contribute to resistance to endocrine and cytotoxic agents through its involvement in cell proliferation and DNA repair.
|
|---|
