Skp2 overexpression is associated with loss of BRCA2 protein in human prostate cancer

Arnaldo A. Arbini, Margherita Greco, Jorge L. Yao, Patricia Bourne, Ersilia Marra, Jer Tsong Hsieh, Paul A. Di Sant'Agnese, Loredana Moro

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18 Scopus citations

Abstract

BRCA2 (breast cancer 2, early onset) is a tumor suppressor gene that confers increased susceptibility for prostate cancer (PCa). Previous in vitro experiments demonstrated that Skp2, an E3 ubiquitin ligase aberrantly overexpressed in PCa, is involved in the proteolytic degradation of BRCA2 in PCa cells, suggesting that the BRCA2-Skp2 interaction may play a role in prostate tumorigenesis. Herein, we investigated BRCA2 and Skp2 expression during PCa development using a prostate TMA. Although luminal and basal benign prostate epithelium exhibited moderate to strong nuclear BRCA2 immunostaining, the intensity and number of positive nuclei decreased significantly in high-grade prostatic intraepithelial neoplasia and PCa. Decreased frequency and intensity of nuclear BRCA2 labeling were inversely correlated with Skp2 expression in high-grade prostatic intraepithelial neoplasia and PCa. To functionally assess the effects of BRCA2 and Skp2 expression on prostate malignant transformation, we overexpressed Skp2 in normal immortalized prostate cells. Skp2 overexpression reduced BRCA2 protein and promoted cell growth and migration. A similar phenotype was observed after reduction of BRCA2 protein levels using specific BRCA2 small-interfering RNA. Forced BRCA2 expression in Skp2-overexpressing stable transfectants inhibited the migratory and growth properties by >60%. These results show that loss of BRCA2 expression during prostate tumor development is strongly correlated with both migratory behavior and cancer growth and include Skp2 as a BRCA2 proteolytic partner in vivo.

Original languageEnglish (US)
Pages (from-to)2367-2376
Number of pages10
JournalAmerican Journal of Pathology
Volume178
Issue number5
DOIs
StatePublished - May 2011

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Arbini, A. A., Greco, M., Yao, J. L., Bourne, P., Marra, E., Hsieh, J. T., Di Sant'Agnese, P. A., & Moro, L. (2011). Skp2 overexpression is associated with loss of BRCA2 protein in human prostate cancer. American Journal of Pathology, 178(5), 2367-2376. https://doi.org/10.1016/j.ajpath.2011.01.050