The human prostate gland is dependent on circulating testosterone for growth, development, and maintenance in men throughout their lifespan. In early stages of prostate cancer, the prostate epithelial cells express androgen receptor (AR) and rely on testosterone for growth and proliferation. At this stage, the cancer is localized and can be treated easily. One of the most common treatments that has been used for over 50 years is androgen deprivation therapy (ADT), which kills epithelial cells that express AR, giving the patient a very high regression rate. Unfortunately, this disease relapses several years later and when this occurs, the disease is non-responsive to ADT and termed castration-resistant prostate cancer (CRPC). Interestingly, a large percentage of these tumor cells express a mutated form of AR or have higher expression of AR and still depend of AR for survival. Furthermore, this is complemented with increased expression of transmembrane heterodimeric adhesion proteins called integrins and migratory proteins that lead to prostate cancer metastasis, for which there is no cure. Recent studies showing that depletion of AR in metastatic prostate cancer cells can lead to the death of these prostate tumor cells suggest that AR is vital for the survival of even CRPC. To build upon this finding and establish a prostate cancer model that closely resembles what is observed in the metastatic disease, we generated several cell line models in which AR expression in a metastatic prostate cancer cell line causes the cells to behave like hormone-refractory tumors in that they do not respond to androgen. Within this model there was a drastic increase in androgen-independent, but AR-dependent, tumor cell survival and a drastic increase in integrin α6β1 with a concomitant decrease in β4 integrin, all of which is observed clinically in patients with CRPC. We also observed an AR-dependent increase in the level of non-receptor tyrosine kinase Src activity as well as its downstream effector proteins and proteases that are crucial in tumor cell migration and tumor cell escape respectively. With these findings, we hypothesized that AR plays an essential role in both the survival and invasiveness of prostate cancer. We propose that tumor survival is driven through a classical nuclear regulation pathway and a novel intracellular and non-nuclear signaling mechanism promotes the aberrant cellular behavior leading to enhanced migration and invasion. In this dissertation I will test this idea in our cell models to establish the importance of these novel pathways. Prostate cancer is a disease that afflicts our fathers, uncles, brothers, nephews, cousins, neighbors, and loved ones. Usually, these men when over the age of 50 will be affected. As stated above, the metastatic and castration-resistant disease is untreatable and will ultimately lead to death. Since it is the metastatic and lethal disease that ultimately leads to death, the proposed studies will potentially help all of these men that suffer from lethal disease by targeting AR, Src, and integrin α6β1 with therapeutic inhibitors that may suppress prostate cancer tumors from surviving and migrating. With the understanding of how these signaling proteins are increased during prostate cancer progression and eventual metastasis, these studies will be applicable to treat disease using drugs that will target these signaling proteins.
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