Estrogens decrease gamma-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 E(2) 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.

Sequence- and concentration-dependent effects of acute and long-term exposure to the bisphosphonate ibandronate in combination with single and multiple fractions of ionising radiation doses in human breast cancer cell lines.

Both bisphosphonates and radiotherapy are highly effective for the management of bone metastases. Our in vitro study examined the cytotoxic effects resulting from combinations of ibandronate and ionising radiations (RX) in various sequences on breast cancer cells. Single radiation doses were given before, at halftime of, or after acute ibandronate incubation (48 h). Single or fractionated radiation doses were applied at the end of chronic ibandronate incubation (5 weeks). Combination of acute ibandronate exposure and single radiation doses led to synergistic cytotoxic effects in MDA-MB-231 cell line, but only with low ibandronate concentrations in MCF-7 cell line. In both cell lines, synergy was more marked when ibandronate followed RX. After long-term ibandronate exposure, only high single radiation doses induced synergistic effects in MDA-MB-231 cell line. Synergy was only detected with low ibandronate concentrations in MCF-7 cell line. In both cell lines, fractionated radiation doses exerted similar effects. The combination of ibandronate with radiation can exert synergistic effects on the inhibition of breast cancer cells growth, depending on cell line, drug sequence and dosage. Our data might provide a rationale for associating bisphosphonates and radiotherapy for the treatment of bone metastases from breast cancer.