Most breast cancers are associated with aberrant signaling by the estrogen receptor (ER), a nuclear hormone receptor and transcription factor, and ER-dependent (ER+) breast cancer cells depend on estrogens, such as estradiol (E2), for survival. ER+ breast cancers are treated with tamoxifen or fulvestrant, which are partial and full ER antagonists, respectively. The proapoptotic tumor suppressor protein p53 is mutated most often in ER-independent breast cancers. Although ER+ breast cancer cells contain wild-type p53, chemotherapy-induced apoptosis of these cells is blocked by estrogens. Bailey et al. performed genome-wide analyses and viability and apoptosis assays to examine p53 function in ER+ breast cancer cells. E2 and tamoxifen independently inhibited the apoptosis of ER+ MCF7 breast cancer cells induced by doxorubicin, which activates p53; however, fulvestrant had no such effect. Microarray analysis showed that doxorubicin and E2 had opposing effects on the expression of two sets of genes, with doxorubicin inhibiting and E2 activating the first set of encoding products that stimulate proliferation, whereas doxorubicin activated and E2 inhibited the second set of genes, which encode products that stimulate apoptosis. Chromatin immunoprecipitation assays showed that a subset of these differentially expressed genes contained binding sites for both ER and p53. Gene expression analysis of MCF7 cells treated with E2, doxorubicin, or both showed that ER inhibited the p53-dependent expression of genes that encode proapoptotic products. Tamoxifen had a similar effect to that of E2, whereas fulvestrant failed to inhibit p53-dependent expression of these genes. Gene expression profiling of breast cancers showed that patients who had enhanced expression of genes that are activated by doxorubicin but inhibited by E2 had increased survival rates compared to patients with the opposite profile. Together, these data suggest that an effective breast cancer therapy may involve agents that activate p53 in combination with fulvestrant, rather than tamoxifen, to completely inhibit ER signaling and prevent p53 antagonism.
S. T. Bailey, H. Shin, T. Westerling, X. S. Liu, M. Brown, Estrogen receptor prevents p53-dependent apoptosis in breast cancer. Proc. Natl. Acad. Sci. U.S.A. 109, 18060–18065 (2012). [Abstract] [Full Text]