Estrogens decrease γ-ray-induced senescence and maintain cell cycle progression in breast cancer cells independently of p53

Purpose: Sequential administration of radiotherapy and endocrine therapy is considered to be a standard adjuvant treatment of breast cancer. Recent clinical reports suggest that radiotherapy could be more efficient in association with endocrine therapy. The aim of this study was to evaluate the estrogen effects on irradiated breast cancer cells (IR-cells). Methods and Materials: Using functional genomic analysis, we examined the effects of 17-beta-estradiol (E-2, a natural estrogen) on MCF-7 breast cancer cells. Results: Our results showed that E-2 sustained the growth of IR-cells. Specifically, estrogens prevented cell cycle blockade induced.by gamma-rays, and no modification of apoptotic rate was detected. In IR-cells we observed the induction of genes involved in premature senescence and cell cycle progression and investigated the effects of E2 on the p53/p21(waf1/cip1)/Rb pathways. We found that E-2 did not affect p53 activation but it decreased cyclin E binding to p21(waf1/cip1) and sustained downstream Rb hyperphosphorylation by functional inactivation of p21(waf1/cip1). We suggest that Rb inactivation could decrease senescence and allow cell cycle progression in IR-cells. Conclusion: These results may help to elucidate the molecular mechanism underlying the maintenance of breast cancer cell growth by E-2 after irradiation-induced damage. They also offer clinicians a rational basis for the sequential administration of ionizing radiation and endocrine therapies. (c) 2007 Elsevier Inc.