Generation of a Reporter Library of ERalpha Interacting DNA Sequences

Oestrogens are a group of steroid hormones of which oestradiol is the major form. Oestrogens are present in men and women and some of their main physiological roles involve female and male reproduction, bone metabolism and homeostasis. Oestrogens carry out their actions by diffusing across the cell membrane and binding to their receptor called the oestrogen receptor (ER), of which two types exist, ERα and ERβ. ERs regulate gene expression through the binding of DNA, most notably the estrogen response element (ERE). Breast cancer is the most common malignancy in women in industrialised countries and 65 percent of breast cancers are ER positive. Oestrogen is involved in the growth and differentiation of epithelial cells in the mammary glands, and the mitogenic effects of oestrogens on breast epithelial cells are in part due to increased expression of genes involved in the regulation of the cell cycle. Selective oestrogen receptor modulators (SERMs), including Tamoxifen and ICI 182,780, are compounds that are designed to be effective in breast cancer prevention and treatment as they inhibit the proliferative effects of oestrogen that are mediated through the oestrogen receptor. Tamoxifen binds the ER in breast cancer cells and has an antioestrogenic effect on growth regulatory genes, while ICI 182,780 ICI182, 780 induces ER degradation resulting in a marked reduction in the cellular concentration of ER. The oestrogen receptor binds to EREs to mediate gene expression. However, there are many types of EREs including half site and multiple EREs. It is also known that ER binds co-operatively to other transcription factors also to regulate gene expression