Steroid Receptor Coactivators and Endocrine Treatment in Breast Cancer pp. 35-66
Authors: (Line L. Haugan Moi, Marianne Hauglid Flågeng, Simon Nitter Dankel, Tuyen Hoang, Jennifer Gjerde, Jørn V. Sagen, Ernst A. Lien, Gunnar Mellgren, Institute of Medicine, University of Bergen and The Hormone Laboratory, Haukeland University Hospital, and The University Hospital of North Norway, Tromsø, Norway)
Abstract: Breast cancer is the most frequent malignancy in women in the Western world. Hormone receptor positive breast cancers are managed with endocrine treatment in which the estrogen receptor (ER) is blocked using a selective estrogen receptor modulator (SERM) such as tamoxifen or by targeting the estrogen synthesis using aromatase inhibitors (AIs). Nuclear receptor coactivators have been pointed out as the main determinants of tissue-, cell- and promoter specific effects of tamoxifen, and they are important regulators of ER mediated gene transcription under estrogen deprivation induced by aromatase inhibition. The steroid receptor coactivator (SRC) family comprises SRC-1, SRC-2/TIF-2 and SRC-3/AIB1. Typically they enhance the transcriptional activity of ligand-bound ER by binding to the activation function-2 (AF-2) pocket, and recruit the basal transcription factors and chromatin-remodeling complex, acetyltransferase proteins, methyltransferases and ubiquitin ligases. 4-hydroxytamoxifen works as an ER antagonist by binding to the nuclear receptor and inducing a displacement of helix 12 that blocks binding of coactivators and favors corepressor recruitment. However, high levels of coactivators relative to corepressors may force ER into an active structural conformation where 4-hydroxytamoxifen leads to ER agonistic effects via AF-1 by indirect binding to DNA and recruitment of coactivators. While SRC-1 and SRC-2/TIF-2 are expressed in normal and malignant breast tissue, SRC-3/AIB1 predominates with overexpression in >30% and gene amplification in 5 – 10% of breast cancers. Our recent studies in human breast cancer have shown that treatment with tamoxifen or AIs enhances gene expression of the SRCs. Others have reported that high levels of SRC-1 are associated with nodal involvement and resistance to endocrine treatment. SRC-3/AIB1 and the growth factor receptor HER-2/neu are often coexpressed in breast cancers, and poor response to tamoxifen treatment and reduced disease-free survival are found when tumors overexpress SRC-1 or SRC-3/AIB1 together with HER-2/neu. The SRCs are regulated by post-translational modifications by for instance mitogen activated protein kinases (MAPKs) which operate downstream of HER-2/neu and stabilize and functionally activate SRC proteins, a mechanism which could contribute not only to tamoxifen resistance, but also to estrogen hypersensitivity and resistance to AIs. In summary, steroid receptor coactivators are crucial in ER regulated gene transcription. Accumulated evidence points to an association between coactivator levels, effect of and response to endocrine treatment and long-term outcome in human breast cancer. The SRCs are involved in crosstalk between ER and growth factor pathways that are activated in breast cancer, making coactivators important in breast cancer development and interesting as potential therapeutic targets.
Open Access item.
Click below PDF icon for free download.
This is an Open Access item. Click above PDF icon for free download.