| Urothelium refers to the tissue layer formed by 3-7 layers of urothelial cells that line much of the urinary tract. These cells are susceptible to malignant transformation since they are in contact with noxious urine components for extended periods, and this process is thought to cause more than 90% of bladder cancers. Urine contains concentrated metabolites of natural, synthesized, and environmental steroids. Steroid hormones, particularly 17beta-estradiol and progesterone, are crucial regulators of cell growth, and these hormones are traditionally considered to act via binding to their cognate receptors. This dissertation reports that the two major estrogen receptors (ERs), ERalpha and ERbeta, and the two major progesterone receptors (PRs), PR-A and PR-B are all expressed by urothelial cells. Our data indicate that estrogen induces urothelial cell proliferation, and this effect is modulated by nerve growth factor via its high-affinity receptor, tyrosine kinase A. Progesterone also induces urothelial cell proliferation, and this effect is mediated by epidermal growth factor. To address the mechanism underlying dysregulated growth of bladder cancer cells, we compared expression of ERs in primary urothelial cells with that in immortalized and cancerous urothelial cells and found that immortalized and cancer cells express much higher amounts of ERalpha than primary cells, whereas all these cells express similar levels of ERbeta. In primary urothelial cells, estrogen-induced GI/S transition and cell proliferation is predominantly mediated by ERbeta, and in bladder cancer cells, ERalpha plays a more dominant role. Our data suggest that both ERs contribute to urothelial cell proliferation and increased expression of ERalpha stimulates dysregulated bladder cancer cell growth via induction of cyclin D1 and cyclin E during the early phases of the cell cycle. To investigate cellular processes that may balance estrogen-induced proliferation, we tested the role of GPR3Q, a newly-identified membrane-associated estrogen-binding protein, in urothelial cell proliferation and found that it mediates an inhibitory effect of estrogen on cell growth via down-regulation of c-fos, c-jun, and cyclin D1. These findings may offer new clues to developing novel therapies to reduce the incidence of bladder cancer and resultant progression and mortality while causing fewer adverse effects within other tissues. |
