Family Matters: Collaboration and Conflict Among the Steroid Receptors Raises a Need for Group Therapy.

Antiestrogen therapies targeting the function of estrogen receptor (ER) have been the cornerstone of therapy for ER+ breast cancer for decades. However, as long as these therapies have been in use, it has also been evident that response to antiestrogen therapy is not based solely on ER expression but that other factors modify breast cancer antiestrogen response. Such factors may include ER's relatives in the steroid hormone receptor (HR) family, androgen receptor (AR), progesterone receptor (PR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR). A series of recent studies has demonstrated that these HRs are not bystanders in ER signaling but rather can alter ER genomic binding and subsequent control of target gene expression. For example, PR and GR may "reprogram" ER binding to DNA toward PR/GR sites; androgen receptor may reverse ER gene regulation functions or regulate ER DNA binding. Accordingly, modulation of HR function concurrently with antiestrogen therapy can either improve antiestrogen response or mediate antiestrogen resistance. This highlights the critical need to better understand how other HRs influence ER function, in particular in the context of antiestrogen therapy. This review discusses recent insights into the mechanisms by which HRs can modify ER function and antiestrogen response, as well as pharmacological implications for antiestrogen therapies and potential combined endocrine therapies.