Insights into how phosphorylation of estrogen receptor at serine 305 modulates tamoxifen activity in breast cancer.

Estrogen receptor (ER) is the most important factor in the pathophysiology of breast cancer. Consequently, modulation of ER activity has been exploited to develop drugs against ER + breast cancer, such as tamoxifen, referred to as endocrine therapies. With deeper understanding of ER mechanism of action, posttranslational modifications (PTMs) are increasingly recognized as important in mediating ER activity. Some ER PTMs such as phosphorylation, are studied in the context of ligand-independent ER activity. However, they also play a pivotal role in defining the actions and outcome of the antiestrogen-bound ER. The complexity of these actions is increasing as new PTMs are identified, yet the functional consequences and clinical implications are not fully understood. This review will examine and summarize new emerging mechanistic knowledge and clinical data in breast cancer on how these PTMs affect antiestrogen-ER activity, with an emphasis on phosphorylation of serine 305 (S305). This phosphorylation site represents an integrated hub of oncogenic signaling to modulate ER conformation, dimerization, coregulators, and DNA binding to profoundly reduce sensitivity to endocrine therapy. Consequently, (i) S305 has the potential to become a useful marker of tamoxifen response, and (ii) blocking S305 phosphorylation defines a new therapeutic strategy to overcome tamoxifen resistance in breast cancer.