Estrogen receptor regulation of two genes, prothymosin alpha and quinone reductase, and their contrasting roles in breast cancer

While it is widely accepted that the risk of developing breast cancer is directly related to lifetime estrogen exposure, the role of estrogen in the initiation and progression of breast cancer is not well defined. It has been hypothesized that initiation could result from estrogen metabolism induced DNA damage, while progression may result from estrogen receptor (ER)-mediated proliferation and propagation of such DNA damage. This thesis focuses on two ER target genes, prothymosin alpha (PTα) and quinone reductase (QR), and their roles in these processes.; PTα has no confirmed function but is suspected of playing a role in cell survival, and studies presented here show that PTα is transcriptionally upregulated by estrogen in breast cancer cells. I have also delimited the region of the PTα promoter involved in ERα-mediated transcriptional regulation and identified a novel ERα-binding element. Further studies suggest that PTα plays an important role in E₂-induced breast cancer proliferation.; QR is a detoxifying enzyme and is transcriptionally induced by antiestrogen-bound ERβ. ERβ transcriptional activity at the electrophile response element (EpRE) of the QR promoter is enhanced by additional cofactors, such as the novel EpRE binding protein hPMC2. Not only does QR detoxify exogenous carcinogens and help to maintain the overall redox status of the cell, it can also detoxify reactive estrogen metabolites. I show here that physiological concentrations of estradiol (E₂) cause an increase in oxidative DNA damage in breast cells. This damage is inversely related to QR and ERβ levels and can also be blocked by antiestrogens if ERβ is present. There is also a significant correlation between levels of E₂-induced oxidative DNA damage and the downstream induction of the DNA repair enzyme XPA.; Finally, I present work that phytoestrogens, naturally occurring weak estrogens found in a wide variety of plant products, induce QR transcription in a manner similar to antiestrogens. Functional studies have also shown that certain phytoestrogens protect against E₂-induced oxidative DNA damage in breast cancer cells. Thus, upregulation of QR by antiestrogens and phytoestrogens may contribute to the proposed protective effects of these substances against breast cancer.