TGFBR3 is lost in prostate cancer, contributing to malignant transformation.

14552 Background: Resistance to transforming growth factor-beta (TGF-beta) is common in solid tumors. Alterations of TGF-beta biology in prostate cancer are complex, with a downregulation of this cytokine reported in early disease and upregulation of TGF-beta in advanced disease. Mechanisms of TGF-beta resistance in early disease are not well understood. We have investigated the function of TGF-beta receptor 3 (TGFBR3) to determine its role in prostate cancer.,We undertook an analysis of the data in seven published DNA microarray studies of nonneoplastic prostate tissue versus prostate cancer specimens using oncomine. Of the genes we identified as known to be directly involved in the TGF-beta pathway, loss of TGFBR3 was most significantly associated with prostate cancer. We determined TGFBR3 expression in prostate cancer cell lines and the immortalized prostate epithelial cell line RWPE-1. To assess the consequences of loss of TGFBR3 expression, we created an shRNA construct and stably infected RWPE-1 cells. We analyzed gene expression changes by DNA microarray analysis and confirmed changes by Western Blot. We then searched TGFBR3 regulated genes based on our knockdown studies in the data set from the seven previously published studies. Furthermore, we evaluated the phenotypic consequences of TGFBR3 knockdown.,TGFBR3 expression was significantly lost in 6 of 7 microarray studies. TGFBR3 was downregulated in 3 of 4 of prostate cancer cell lines, compared with RWPE-1. DNA microarray analysis of TGFBR3 knockdown in RWPE-1 cells showed that expression of DPYSL3, Vimentin, COCH, SERPINF1, PMP22, LTBP1 and BMP4 were decreased both with TGFBR3 knockdown and in the transition to prostate cancer. Of these genes, vimentin expression was most dramatically downregulated in TGFBR3 knockdown cells and we showed that vimentin protein expression was completely lost. The phenotypic consequence of TGFBR3 knockdown in RWPE-1 cells was formation of colonies that appear to reflect loss of contact inhibition.,TGFBR3 is lost in prostate cancer. TGFBR3 knockdown leads to colony formation by immortalized prostate epithelial cells. Our data suggests that loss of TGFBR3 contributes to malignant transformation of the prostate. No significant financial relationships to disclose.