We have conducted translational research to understand the genetic and molecular mechanism that govern prostate cancer development and progression, to identify novel pathways for drug development, and investigate mechanisms of resistance to treatment paradigms. We have a longstanding collaboration with the Prostate Cancer Prevention Trial (PCPT) investigators to elucidate the molecular and genetic mechanisms that may help explain the trial outcomes of the PCPT. The overall goals of this project are: a) to better understand associations between important androgen regulatory gene polymorphisms and CaP risk; and b) to evaluate the effects of these polymorphisms and serum hormone concentrations on the use of finasteride as a chemopreventive agent for CaP. Metabolism and transport play major roles in lifelong exposure to endogenous and exogenous carcinogens. We therefore explored associations between polymorphisms in absorption, distribution, metabolism and elimination genes and the risk and prognosis of castration-resistant prostate cancer (CRPC). A total of 634 genotypes were tested in 74 patients using the Affymetrix DMETv1.0 platform. While no relation to risk was found, several associations were noted between CPPC prognosis and transporters that regulate bodily sterol and fatty-acid disposition. Three SNPs in the major bile-flow transporters were associated with CRPC prognosis in Caucasians: ABCB11 rs7602171 (bile salt export pump; p = 0.003; hazard ratio [HR]: 0.307), GSTP1 rs1799811CT (glutathione S-transferase pi; p = 0.001; HR: 0.254) and SLC5A6rs1395 (sodium dependent-vitamin transporter; p = 0.004; HR: 3.15). Two other polymorphisms among Caucasians were associated with interesting trends: ABCB4 rs2302387 (phosphatidyl-choline floppase, MDR3; p = 0.039) and ABCC5 rs939339 (p = 0.018). This exploratory study is the first to show that polymorphisms in several absorption, distribution, metabolism and elimination genes may be associated with CRPC prognosis. We are also interested in understanding the molecular genetics of androgen transport. The organic anion transporter OATP1B3, encoded by SLCO1B3, is involved in the transport of steroid hormones. We have shown that prostate cancer overexpresses OATP1B3 compared to normal or benign hyperplastic tissue, and the common SLCO1B3 GG/AA haplotype is associated with impaired testosterone transport and improved survival in patients with CaP. We found that a polymorphism in this transporter increases testosterone import is associated with a shorter time to androgen independence in patients with CaP who are treated with ADT. Castration-resistant prostate cancer (CRPC) has greater intratumoral testosterone concentrations than similar tumors from eugonadal men; simple diffusion does not account for this observation. We recently conducted studies to ascertain the androgen uptake kinetics, functional, and clinical relevance of de novo expression of OATP1B3. We found that de novo OATP1B3 expression in prostate cancer drives greater androgen uptake and is consistent with previous observations that greater OATP1B3 activity results in the development of androgen deprivation therapy resistance and shorter overall survival. Studies are ongoing to characterize the molecular mechanisms of SLCO1B3 transcription and whether the genetics of the OATP1B3 transporter influences the outcome of prostate cancer patients on androgen deprivation therapy.
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