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β₁ Integrin Cytoplasmic Variants Differentially Regulate Expression of the Antiangiogenic Extracellular Matrix Protein Thrombospondin 1

¹ Department of Cancer Biology, Prostate Cancer Discovery and Development Program, and ² Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts; ³ Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; and ⁴ Departments of Pathology and Urology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

Requests for reprints: Lucia R. Languino, Department of Cancer Biology, Prostate Cancer Discovery and Development Program, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605. Phone: 508-856-1606; Fax: 508-856-1310; E-mail: lucia.languino{at}umassmed.edu.

Key Words: β₁ integrin variants • thrombospondin • prostate cancer • laminin • extracellular matrix

β₁ integrins play an important role in regulating cell proliferation and survival. Using small interfering RNA or an inhibitory antibody to β₁, we show here that, in vivo, β₁ integrins are essential for prostate cancer growth. Among the five known β₁ integrin cytoplasmic variants, two have been shown to differentially affect prostate cell functions. The β_1A variant promotes normal and cancer cell proliferation, whereas the β_1C variant, which is down-regulated in prostate cancer, inhibits tumor growth and appears to have a dominant effect on β_1A. To investigate the mechanism by which β_1C inhibits the tumorigenic potential of β_1A, we analyzed changes in gene expression in cells transfected with either β_1C or β_1A. The results show that β_1C expression increases the levels of an extracellular matrix protein, thrombospondin 1 (TSP1), an angiogenesis inhibitor. TSP1 protein levels are increased upon β_1C expression in prostate cancer cells as well as in β₁-null GD25 cells. We show that TSP1 does not affect proliferation, apoptosis, or anchorage-independent growth of prostate cancer cells. In contrast, the newly synthesized TSP1, secreted by prostate cancer cells expressing β_1C, prevents proliferation of endothelial cells. In conclusion, our novel findings indicate that expression of the β_1C integrin variant in prostate glands prevents cancer progression by up-regulation of TSP1 levels and inhibition of angiogenesis. [Cancer Res 2009;69(13):5374–82]