HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 29, 27022-27028, July 22, 2005

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 280/29/27022    most recent M505071200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, Q. Articles by Cao, X. Search for Related Content PubMed PubMed Citation Articles by Li, Q. Articles by Cao, X. Social Bookmarking                      What's this?

Smad4 Inhibits Tumor Growth by Inducing Apoptosis in Estrogen Receptor--positive Breast Cancer Cells^*

Qingnan Li¶, Liyu Wu, Denise K. Oelschlager, Mei Wan, Cecil R. Stockard, William E. Grizzle, Ning Wang, Huaiqing Chen¶, Yi Sun, and Xu Cao||

From the Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, the Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, China, and the ^¶Institute of Biomedical Engineering, West China Center of Medical Sciences, Sichuan University, Chengdu, Sichuan 610041, China

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

Received for publication, May 9, 2005

^* This work was supported by Department of Defense Grant BC010975 (to X. C.) and National Institutes of Health Grant DK60913 (to X. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. 1S and 2S.

^|| To whom correspondence should be addressed: Dept. of Pathology, University of Alabama at Birmingham, 1670 University Blvd., VH G003, Birmingham, AL 35294-0019. Tel.: 205-934-0162; Fax: 205-934-1775; E-mail: cao{at}path.uab.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. E Burdette and T. K Woodruff Activin and estrogen crosstalk regulates transcription in human breast cancer cells Endocr. Relat. Cancer, September 1, 2007; 14(3): 679 - 689. [Abstract] [Full Text] [PDF]

				N. Heldring, A. Pike, S. Andersson, J. Matthews, G. Cheng, J. Hartman, M. Tujague, A. Strom, E. Treuter, M. Warner, et al. Estrogen Receptors: How Do They Signal and What Are Their Targets Physiol Rev, July 1, 2007; 87(3): 905 - 931. [Abstract] [Full Text] [PDF]