β 1 integrins play an important role in regulating cell proliferation and survival. Using small interfering RNA or an inhibitory antibody to β 1 , we show here that, in vivo, β 1 integrins are essential for prostate cancer growth. Among the five known β 1 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 β 1 -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. ©2009 American Association for Cancer Research.