TGFBETA Signaling in Prostate Cancer Cells

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PROJECT SUMMARY (See instructions): African-American men are disproportionately affected by prostate cancer. African-American men have 65% higher incidence rate and more than twice the mortality rate due to prostate cancer when compared with Caucasian men. Prostate cancer is also diagnosed at a more advanced stage at an earlier age in African- American men. Previous studies in breast and endometrial cancer suggested an important role of TGF Beta3 (vs TGF Beta1) in metastatic disease. Recent studies have shown that peripheral blood TGF-Beta1 protein levels are associated with body mass index, microalbumuria, plasma renin activity, and metabolic syndrome in African Americans but not in Caucasians. Overexpression of TGF-Beta1 was significantly higher in African- Americans patients than in Caucasian patients with hypertension, diabetes, glaucoma and end stage renal disease. In our recent studies, we determined the expression of three TGF-B isoforms (-B1, B2 and B3) in several prostate cell lines representing normal epithelial cells and various stages of cancer progression. These studies revealed that TGF-Beta1 mRNA and protein were expressed by all cell lines. On the other hand, TGF- Beta3 mRNA and protein are expressed at very low levels in normal prostate epithelial cells but are expressed at very high levels in prostate cancer cell lines representing metastatic stages of the disease. Our continued studies revealed that TGF- Beta3 exerts significant effects on migration and invasive behavior of prostate cancer cells and that this isoform is significantly more potent than TGF- Beta3 in exerting these effects. We also found that these effects of TGF- Beta3 on migration and invasion are mediated by the Beta3-kinase/AKT signaling pathway. The studies proposed in this grant will test the hypothesis that the increased expression of TGF- Beta3 in later stages of cancer may be involved in rapid progression of the metastatic disease. Additionally, higher levels of this cytokine in African-American men may be responsible for increased incidence and mortality due to prostate cancer. These studies will focus on 1) determination of the expression of TGF- Beta isoforms, 2) the activation of PI3-kinase signaling pathway by TGF- Beta3 and, 3) the mechanisms by which TGF-Beta may regulate the invasive behavior of prostate cancer cells.