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J. Biol. Chem., Vol. 280, Issue 23, 22482-22491, June 10, 2005

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Down-regulation of BRCA2 Expression by Collagen Type I Promotes Prostate Cancer Cell Proliferation^*

Loredana Moro¶, Arnaldo A. Arbini, Ersilia Marra, and Margherita Greco

From the Institute of Biomembranes and Bioenergetics, National Research Council (Consiglio Nazionale delle Ricerche), Bari 70126, Italy and the Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

BRCA2 is a tumor suppressor gene that when mutated confers an increased susceptibility to developing breast and prostate carcinoma. Besides its role in mediating DNA repair, new evidence suggests that BRCA2 may also play a role in suppressing cancer cell growth. Because altered interactions between neoplastic cells and the surrounding extracellular matrix (ECM) play a pivotal role in unchecked cancer cell proliferation and metastatic progression, we hypothesized that the ECM may have an effect in BRCA2 expression. By using normal and prostate carcinoma cell lines, we demonstrated that although normal cells transiently increase BRCA2 protein levels when adhering to the ECM protein collagen type I (COL1), carcinoma cells exhibit a significant reduction in BRCA2 protein. This aberrant effect is independent from de novo protein synthesis and results from COL1-₁ integrin signaling through phosphatidylinositol (PI) 3-kinase leading to BRCA2 ubiquitination and degradation in the proteasome. BRCA2 protein depletion after cancer cell adhesion to COL1 or in small RNA interference assays triggers new DNA synthesis, a trophic effect that is abrogated by recombinant BRCA2 expression. Blocking or inhibiting ₁ integrin, PI 3-kinase, or proteasome activity all have a negative effect on COL1-mediated DNA synthesis in cancer cells. In normal cells, the transient increase in BRCA2 expression is independent from ₁ integrin or PI 3-kinase and has no effect in cell proliferation. In summary, these results unravel a novel mechanism whereby prostate carcinoma cell proliferation is enhanced by the down-regulation of BRCA2 expression when interacting with COL1, a major component of the ECM at osseous metastatic sites.

Received for publication, December 15, 2004 , and in revised form, March 29, 2005.

^* This work was supported by the MURST-PPRST Cluster 03 Grant and the MIUR-Contributi Straordinari di Ricerca/Aree Obiettivo 1 Grant (to E. M.). 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.

^¶ To whom correspondence should be addressed: Institute of Biomembranes and Bioenergetics, National Research Council (Consiglio Nazionale delle Ricerche), Via Amendola 165/A, 70126 Bari, Italy. Tel.: 39-080-544-2412; Fax: 39-080-544-3317; E-mail: l.moro{at}ibbe.cnr.it.

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This article has been cited by other articles:

				L. Moro, A. A. Arbini, E. Marra, and M. Greco Up-regulation of Skp2 after Prostate Cancer Cell Adhesion to Basement Membranes Results in BRCA2 Degradation and Cell Proliferation J. Biol. Chem., August 4, 2006; 281(31): 22100 - 22107. [Abstract] [Full Text] [PDF]