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J. Biol. Chem., Vol. 283, Issue 42, 28354-28360, October 17, 2008

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Breast Cancer Metastasis Suppressor-1 Differentially Modulates Growth Factor Signaling^*

Kedar S. Vaidya¹, Sitaram Harihar², Pushkar A. Phadke³, Lewis J. Stafford, Douglas R. Hurst⁴, David G. Hicks^¶, Graham Casey^¶, Daryll B. DeWald, and Danny R. Welch^||**5

From the Departments of Pathology, ^||Cell Biology, and ^**Pharmacology and Toxicology, the Comprehensive Cancer Center, and the National Foundation for Cancer Research Center for Metastasis Research, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, the Department of Biology, Utah State University, Logan, Utah 84322, and the ^¶Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Lerner School of Medicine, Cleveland, Ohio 44195

That metastatic tumor cells grow in selective non-native environments suggests an ability to differentially respond to local microenvironments. BRMS1, like other metastasis suppressors, halts ectopic growth (metastasis) without blocking orthotopic tumor formation. BRMS1-expressing tumor cells reach secondary sites but do not colonize distant tissues, compelling the hypothesis that BRMS1 selectively restricts the ability of tumor cells to respond to exogenous regulators in different tissues. Here we report that BRMS1 expression in metastatic human breast cancer cells leads to a selective reduction in epidermal growth factor receptor expression and downstream (AKT) signaling. Signaling through another receptor tyrosine kinase, hepatocyte growth factor receptor (c-Met), remains unaltered despite reduced levels of the signaling intermediate phosphatidylinositol (4,5)-bisphosphate. Interestingly, reduced downstream calcium signaling is observed following treatment with platelet-derived growth factor, consistent with decreased phosphatidylinositol (4,5)-bisphosphate. However, platelet-derived growth factor receptor expression is unaltered. Thus, BRMS1 differentially attenuates cellular responses to mitogenic signals, not only dependent upon the specific signal received, but at varying steps within the same signaling cascade. Specific modulation of signaling responses received from the microenvironment may ultimately dictate which environments are permissive/restrictive for tumor cell growth and provide insights into the biology underlying metastasis.

Received for publication, December 10, 2007 , and in revised form, July 28, 2008.

^* This work was supported in part by United States Public Health Service Grant R01-CA87728, United States Army Medical Research and Materiel Command Grant DAMD-17-02-1-0541, and the National Foundation for Cancer Research Center for Metastasis Research (to D. R. W.). 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. 1 and 2 and Table 1.

¹ Supported by Postdoctoral Fellowship PDF1122006 from Susan G. Komen for the Cure.

² Performed this work in partial fulfillment of the requirements of the doctoral program at the Utah State University.

³ Performed this work in partial fulfillment of the requirements of the doctoral program at the University of Alabama at Birmingham.

⁴ Supported by United States Public Health Service Ruth L. Kirschstein National Research Service Award F32CA113037.

⁵ To whom correspondence should be addressed: University of Alabama at Birmingham, G-019 Volker Hall, 1670 University Blvd., Birmingham, AL 35294-0019. Tel.: 205-934-2956; Fax: 205-975-1126; E-mail: DanWelch{at}uab.edu.

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