Regulation of cancer cell proliferation and survival by β 1 integrins

M. Fornaro,PhD, Duo-Qi Zheng, MD PhD, Michela Manzotti, PhD,a, Giovanni Tallini, MD, and Lucia R. Languino, PhD.

Department of Pathology, Yale University School of Medicine, New Haven, CT 06520 and a Department of Pathology, European Institute of Oncology, MD20141 Milan, Italy.

AIM: Alterations of integrin expression in cancer affect tumor growth. The Beta 1C integrin is a cytoplasmic domain variant of the Beta 1 subfamily. At variance with Beta 1A, Beta 1C inhibits in vitro cancer cell proliferation and in vivo, it is selectively downregulated in prostatic adenocarcinoma. A potential correlation of expression of Beta 1C and of the cyclin kinase inhibitor p27kip1 in vivo in benign and neoplastic prostate tissues as well as Beta 1C downstream signaling pathways that control cancer cell proliferation and survival were studied. METHODS: Tissue microarray technology, conventional immunohistochemistry and immunoblotting analysis were employed to investigate the expression of Beta 1C and p27 kip1 in prostatic adenocarcinoma. Biochemical assays were performed to analyze Beta 1C modulation of signaling pathways involved in the control of cell cycle progression and survival. RESULTS: A very high correlation of Beta 1C and p27kip1 expression was found in 93% of benign cells and in 84-91% of neoplastic cells of the analyzed specimens (p<0.0001). In 75% of the specimens analyzed, both Beta 1C and p27kip1 were downregulated in tumor areas in comparison to benign counterparts. In contrast to Beta 1A, forced expression of Beta 1C in vitro was accompanied by an increase in p27kip1 levels, by inhibition of cyclin A-dependent kinase activity and of the Ras/MAP kinase pathway. Furthermore, Beta 1C sensitized cells to drug-induced apoptosis. Beta 1C inhibitory effect on cell proliferation and survival was completely prevented by p27kip1 antisense or by expression of activated Ras and MAP kinase. CONCLUSIONS: These results indicate that Beta 1C may be a sensitive prognostic indicator of potential high clinical value to predict therapy and patient survival for prostatic adenocarcinoma and that the Beta 1C integrin, via a unique signaling mechanism, controls cancer cell proliferation and survival.

KEY WORDS: adhesion, cancer, integrin cytoplasmic domain, cyclin-dependent kinase inhibitors.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Prognostic Markers.