Prostate cancer is among the leading causes of cancer-related death of men in Western countries. Strategies for its primary prevention through nutritional modifications have recently become a major focus. There is substantial epidemiologic evidence that an excess of dietary calcium, mainly from dietary sources, increases the risk of prostate cancer. The exact biological basis for this, however, is unknown. One possible explanation is that calcium can reduce the body's level of 1,25-vitamin D3 which has been shown to protect the prostate, but various scientists have questioned the significance of this concept. Understanding the molecular properties of calcium channels, including their regulation by 1,25-vitamin D3, may help explain the role of the nutrient calcium in prostate cancer development. Calcium channels play a important roles in the metabolism of prostate cancer epithelial cells but little is known about their implications in prostate cancer development. We propose to investigate the role of the epithelial calcium entry channel, CaT1 (TRPV6), and other calcium permeable channels in prostate cancer malignancy. Our laboratory has recently demonstrated that CaT1 is upregulated several fold in prostate malignancy, indicating that it might be involved in proliferation and tumor cell growth. To investigate the relationship of dietary calcium, calcium channels and prostate cancer risk, we propose to study the following: (1) The regulation of CaT1 in response to high and low calcium diets in various prostate cancer cell lines, the prostates of control mice and the prostate carcinomas of TRAMP (transgenic adenocarcinoma of mouse prostate) mice. (2) The effect of reduced expression of CaT1 on tumor progression by crossing the TRAMP mouse with the CaT1 (+/-) or CaT1 (-/-) mouse. (3) The implication of the level of CaT1 expression in regulating proliferation and apoptosis in prostate cancer cells. (4) The molecular identity, biophysical properties and roles in prostate tumor progression of other putative calcium channel proteins. Since the human body depends on dietary calcium intake to maintain the integrity of the skeleton, dietary calcium restriction would not be appropriate to reduce the risk of prostate cancer. The molecular characterization of CaT1 and related calcium channels, however, may lead to alternative strategies for the treatment of prostate cancer, involving inhibition of calcium influx into prostate cancer cells to impair tumor growth.
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