Estrogen is a mitogen in most estrogen receptor-alpha (ER alpha)-positive breast cancers. We have found that Smad4, a common signal transducer in the transforming growth factor-beta superfamily, acts as an ER alpha transcriptional corepressor. Here, we show that Smad4 induces apoptosis in ER alpha-positive MCF-7 breast cancer cells, but not in ER alpha-negative MDA-MB-231 cells. Smad4 induced expression of short Bim isoforms ( by alternative splicing) and Bax and release of cytochrome c in ER alpha-positive cells only, and expression of these apoptotic marker genes was reduced when ER alpha small interfering RNA was introduced. Notably, Smad4 was able to induce apoptosis in MDA-231 cells with acquired ER alpha expression. Furthermore, Smad4 inhibited ER alpha-positive tumor growth by inducing apoptosis in tumor xenografts in nude mice. The sizes of tumors expressing Smad4 were only one-tenth the size of those expressing green fluorescent protein, whereas in ER alpha-negative cells, Smad4 did not reduce the tumor size. Notably, Smad4 also promoted short Bim isoform and Bax expression and release of cytochrome c only in ER alpha-positive MCF-7 tumor xenografts. Bim was sufficient for induction of apoptosis, and the short form was the most potent inducer. Our results demonstrate that Smad4 induces apoptosis by regulating Bim splicing as an initial intrinsic signal in ER alpha-positive cells. Smad4-induced apoptosis in ER alpha-positive breast cancer cells may explain the invasive nature of ER alpha-negative breast tumors, thereby providing a potential target for breast cancer intervention.
Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA;Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Urumqi 830011, Peoples R China;W China Ctr Med Sci, Inst Biomed Engn, Chengdu 610041, Sichuan, Peoples R China
Li, GG,Wu, LY,OElschlager, DK,et al. Smad4 inhibits tumor growth by inducing apoptosis in estrogen receptor-alpha-positive breast cancer cells[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2005,280(29):27022-27028.