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Metastasis Suppression by Breast Cancer Metastasis Suppressor 1 Involves Reduction of Phosphoinositide Signaling in MDA-MB-435 Breast Carcinoma Cells

¹ Department of Biology, Utah State University, Logan, Utah; ² National Foundation for Cancer Research, Center for Metastasis Research; ³ Jake Gittlen Research Institute, The Pennsylvania University College of Medicine, Hershey, Pennsylvania; and ⁴ Department of Pathology, Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama

Requests for reprints: Danny R. Welch, Department of Pathology, University of Alabama at Birmingham, 1670 University Drive, Volker Hall, Room G019A, Birmingham, AL 35294-0019. Phone: 205-934-2956; Fax: 205-975-1126; E-mail: dwelch{at}path.uab.edu or Daryll B. DeWald, 5305 University Blvd., Logan, UT 84322-5305. Phone: 435-797-3711; E-mail: dewald{at}biology.usu.edu.

Several molecules that suppress metastasis without suppressing tumorigenicity have been identified, but their mechanisms of action have not yet been determined. Many block growth at the secondary site, suggesting involvement in how cells respond to signals from the extracellular milieu. Breast cancer metastasis suppressor 1 (BRMS1)–transfected MDA-MB-435 cells were examined for modifications of phosphoinositide signaling as a potential mechanism for metastasis suppression. 435/BRMS1 cells expressed <10% of phosphatidylinositol-4, 5-bisphosphate compared with parental cells, whereas levels of the PtdIns(4)P and phosphatidylinositol-3-phosphate were unchanged. Inositol (1,4,5)-trisphosphate [Ins(1,4,5)P₃] were decreased in 435/BRMS1 cells by 50%. Phosphatidylinositol-3,4,5-trisphosphate levels were undetectable in 435/BRMS1 cells, even when stimulated by exogenous insulin or platelet-derived growth factor. Immunofluorescence microscopy to examine cellular distribution confirmed that phosphatidylinositol-4,5-bisphosphate distribution with cells was unchanged but was uniformly decreased throughout the cell. Although the gross morphology of 435/BRMS1 cells is similar to the parent, filamentous actin was more readily apparent in 435/BRMS1. Intracellular calcium, measured using Fluo-3 and Fura-2 fluorescent calcium indicator dyes, was somewhat lower, but not statistically different in 435/BRMS1 compared with parental cell. However, when stimulated with platelet-derived growth factor, MDA-MB-435 cells, but not 435/BRMS1 cells mobilized intracellular calcium. Taken together, these results implicate signaling through phosphoinositides in the regulation of breast cancer metastasis, specifically metastasis that can be suppressed by BRMS1.

Key Words: metastasis suppressor gene • microenvironment • tumor-host interactions • cell signaling

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