Estrogen receptor alpha phosphorylation and its functional impact in human breast cancer

Estrogen receptor alpha (ER alpha) is a member of the nuclear receptor superfamily of transcription factors that regulates cell proliferation, differentiation and homeostasis in various tissues. Sustained exposure to estrogen/estradiol (E2) increases the risk of breast, endometrial and ovarian cancers. ER alpha function is also regulated by phosphorylation through various kinase signaling pathways that will impact various ER alpha functions including chromatin interaction, coregulator recruitment and gene expression, as well impact breast tumor growth/morphology and breast cancer patient response to endocrine therapy. However, many of the previously characterized ER alpha phosphorylation sites do not fully explain the impact of receptor phosphorylation on ER alpha function. This review discusses work from our laboratory toward understanding a role of ER alpha site-specific phosphorylation in ER alpha function and breast cancer. The key findings discussed in this review are: (1) the effect of site specific ER alpha phosphorylation on temporal recruitment of ER a and unique coactivator complexes to specific genes; (2) the impact of stable disruption of ER alpha S118 and S167 phosphorylation in breast cancer cells on eliciting unique gene expression profiles that culminate in significant effects on breast cancer growth/morphology/migration/invasion; (3) the Src kinase signaling pathway that impacts ER alpha phosphorylation to alter ER alpha function; and (4) circadian disruption by light exposure at night leading to elevated ERK1/2 and Src kinase and phosphorylation of ER alpha, concomitant with tamoxifen resistance in breast tumor models. Results from these studies demonstrate that even changes to single ER alpha phosphorylation sites can have a profound impact on ER alpha function in breast cancer. Future work will extend beyond single site phosphorylation analysis toward identification of specific patterns/profiles of ER alpha phosphorylation under different physiological/pharmacological conditions to understand how common phosphorylation profiles in breast cancer program specific physiological endpoints such as growth, apoptosis, migration/invasion, and endocrine therapy response. (C) 2015 Elsevier Ireland Ltd. All rights reserved.