Purpose. Sequential administration of radiotherapy and endocrine therapy is considered as 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).
Materials and Methods. Using functional genomic analysis, we have dissected the effects of 17-beta-estradiol (E2, a natural estrogen) on MCF-7 breast cancer cells (BCC).
Results. E2 sustained the growth of IR-cells. More precisely, estrogens prevented cell cycle blockade induced by gamma-rays; moreover, no modification of apoptotic rate was detected. In IR-cells, we observed the induction of genes involved in premature senescence and cell cycle progression. We, then, focused our investigations on the effects of E2 on the P53/P21waf1/cip1/Rb pathways. Indeed, E2 did not affect P53 activation but it decreased cyclin E binding to P21waf1/cip1 and sustained downstream Rb hyper-phosphorylation by functional inactivation of P21waf1/cip1. We suggest that Rb inactivation could decrease senescence and allow cell cycle progression in IR-cells.
Conclusion. These results may help to understand the molecular mechanism underlying the maintenance of breast cancer cell growth by E2 after irradiation-induced damage. They also offer to the clinicians a rational basis for the sequential administration of ionizing radiation and endocrine therapies.
