Estrogen and antiestrogen regulation of genes in human endometrial and breast cancer cell lines

Breast and Endometrial cancer are two of the most common cancer in women in North America and breast cancer is one of the leading causes of premature death in women. Lifetime exposure to estrogen or estrogen like compounds is common risk factors for both breast and endometrial cancers however there are major differences in regulation of hormone-dependent genes in breast and endometrial cancer cells. For example, tamoxifen a widely used antiestrogenic drug for treatment and prevention of breast cancer is a weak estrogen receptor α (ERα) agonist in the uterus and increases the risk for endometrial cancer. The tissue-specific difference in the activity of tamoxifen has been linked to activation function 1 (AF1) of ERα. Research described in this thesis shows that tamoxifen-induced expression of estrogen-responsive genes is highly variable even among breast and endometrial cancer cells and that the ERα agonist and antagonist activity of tamoxifen is dependent on ER-subtype, cell and promoter context. The second project of this research was focused on the molecular biology of transcriptional activation of cyclin D1 gene expression by estrogen in ZR-75 human breast cancer cells. Previous studies in HeLa and MCF-7 cells showed cyclin D1 was induced by E2 only through a CRE site at −58 to −50 in the proximal region of the promoter another report showed that ERα was not necessary for this induction in MDA-MB-231 cells. In our studies we showed two different pathways of induction of cyclin D1 gene by E2 in ZR-75 breast cancer cells. The CRE at −58 to −50 was E2-responsive and the results are consistent with induction of the cAMP/PKA and activation of CREB/ATF1 at the CRE site. The second pathway involved activation of ERα/Sp1 interactions with three Sp1 sites and the possible three GC-rich sites at −133 to −100 in the promoter. This mechanism of CD1 activation by E2 in ZR-75 clearly differed from previous studies in MCF-7 and ZR-75 cells and this demonstrates the importance of cell context in transactivation pathways even between ERα-positive breast cancer cell lines.