Steroid Receptor Coactivators and Their Expression, Regulation and Functional Role in Endocrine Responsive and Resistant Breast Cancer

Breast cancer is the most frequent malignancy and one of the leading causes to cancer related deaths in women. Most human breast cancers express the estrogen receptor (ER) which belongs to the family of nuclear receptors and is a ligand-regulated transcription factor. It is well established that the natural ligand of ER, estrogen, has pro-carcinogenic and growth promoting effects in the mammary epithelium by stimulating proliferation and leaving the cells prone to mutations during cell cycle progression (Foster et al., 2001). Endocrine treatment of hormone sensitive breast cancer targets the estrogen activity in breast cancer cells by blocking the ER with a selective ER modulator (SERM) such as tamoxifen or inhibiting estrogen synthesis using aromatase inhibitors such as anastrozole or letrozole. Endocrine treatment decreases mortality, prolongs disease-free survival and can even reduce the incidence of breast cancer in women at increased risk (Cuzick et al., 2003). Approximately 70 % of women with ER positive tumors respond to endocrine therapy, but resistance do occur, either de novo or develop over time. The molecular mechanism involved in endocrine resistance is one of the central areas of breast cancer research. The trancriptional activity of the ER is not only regulated by its ligands, but also by the level and activity of coregulator proteins. Nuclear receptor coactivators serve as adapters between the receptor and the trancriptional machinery. They possess diverse enzymatic acitivities such as histone acetyltransferase, histone methyltransferase, chromatin remodeling and ubiquitin-conjugation activity and are involved in every step of ER regulated transcription, from chromatin remodeling to transcriptional termination. The members of the p160 family of coactivators are some of the best studied coactivators. These steroid receptor coactivators (SRCs) are small proteins of 160 kDa with similar structural and functional properties, and include SRC-1, SRC-2/transcription intermediary factor-2 (TIF-2) and SRC-3/amplified in breast cancer 1 (AIB1). The SRCs are not only crucial to ER mediated effects in normal tissue. They have also been shown to be involved in the carcinogenic process and are