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Smad4 inhibits tumor growth by inducing apoptosis in estrogen receptor-alpha-positive breast cancer cells
Li Qingnan; Wu Liyu; Oelschlager Denise K.; Wan Mei; Stockard Cecil R.; Grizzle William E.; Wang Ning; Chen Huaiqing; Sun Yi; Cao Xu
2005
Source PublicationJournal of Biological Chemistry
ISSN219258
Volume280Issue:29Pages:27022-27028
Abstract

Estrogen is a mitogen in most estrogen receptor-α (ERα)-positive breast cancers. We have found that Smad4, a common signal transducer in the transforming growth factor-β superfamily, acts as an ERα transcriptional corepressor. Here, we show that Smad4 induces apoptosis in ERα-positive MCF-7 breast cancer cells, but not in ERα-negative MDA-MB-231 cells. Smad4 induced expression of short Bim isoforms (by alternative splicing) and Bax and release of cytochrome c in ERα-positive cells only, and expression of these apoptotic marker genes was reduced when ERα small interfering RNA was introduced. Notably, Smad4 was able to induce apoptosis in MDA-231 cells with acquired ERα expression. Furthermore, Smad4 inhibited ERα-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 ERα-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 ERα-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 ERα-positive cells. Smad4-induced apoptosis in ERα-positive breast cancer cells may explain the invasive nature of ERα-negative breast tumors, thereby providing a potential target for breast cancer intervention.

DOI10.1074/jbc.M505071200
Indexed BySCI
WOS IDWOS:000230589500047
Citation statistics
Document Type期刊论文
Identifierhttp://ir.xjipc.cas.cn/handle/365002/2218
Collection资源化学研究室
AffiliationUniv 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
Recommended Citation
GB/T 7714
Li Qingnan,Wu Liyu,Oelschlager Denise K.,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.
APA Li Qingnan.,Wu Liyu.,Oelschlager Denise K..,Wan Mei.,Stockard Cecil R..,...&Cao Xu.(2005).Smad4 inhibits tumor growth by inducing apoptosis in estrogen receptor-alpha-positive breast cancer cells.Journal of Biological Chemistry,280(29),27022-27028.
MLA Li Qingnan,et al."Smad4 inhibits tumor growth by inducing apoptosis in estrogen receptor-alpha-positive breast cancer cells".Journal of Biological Chemistry 280.29(2005):27022-27028.
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