DNA Repair, Redox Regulation and Modulation of Estrogen Receptor Alpha Mediated Transcription

Interaction of estrogen receptor [alpha] (ER[alpha]) with 17[beta]-estradiol (E[subscript 2]) facilitates binding of the receptor to estrogen response elements (EREs) in target genes, which in turn leads to recruitment of coregulatory proteins. To better understand how estrogen-responsive genes are regulated, our laboratory identified a number of proteins that associate with the DNA-bound ER[alpha]. Our studies demonstrate that the nonmetastatic protein 23 homolog 1 (NM23-H1) interacts with ER[alpha], increases ER[alpha]-ERE complex formation, influences ER[alpha]-mediated transcription and associates with the promoter region of the endogenous estrogen-responsive progesterone receptor (PR) gene. Furthermore, we show that a second protein, Apurinic/apyrimidinic endonuclease 1 or redox factor-1 (Ape1/Ref-1), interacts with ER[alpha], promotes the ER[alpha]-ERE interaction, influences ER[alpha]-mediated transactivation, and selectively associates with endogenous, estrogen-responsive genes in MCF-7 cells. Our findings suggest that NM23-H1 and Ape1/Ref-1 are instrumental in modulating expression of estrogen-responsive genes. Interestingly, we demonstrate that Ape1/Ref-1 and NM23-H1, as well as the oxidative stress proteins Cu/Zn superoxide dismutase (SOD1), thioredoxin (Trx) and protein disulfide isomerase (PDI) are overexpressed in human breast cancer tissues. These studies provide a novel link between DNA repair, redox regulation and modulation of ER[alpha]-mediated transcription. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]