Steroid hormone receptors (SRs) have a multitude of functions in human biology and
disease progression. The SR family of related
ligand-activated
transcription factors includes
androgen,
estrogen,
glucocorticoid,
mineralocorticoid, and
progesterone receptors.
Antiestrogen or
estrogen receptor (ER)-targeted
therapies to block ER action remain the primary treatment of
luminal breast
cancers. Although this strategy is successful, ∼40% of patients eventually relapse due to endocrine resistance. The majority of
hormone-independent
tumors retain some level of SR expression, but sidestep
hormone ablation treatments. SRs are known to crosstalk extensively with
kinase signaling pathways, and this interplay has been shown to bypass ER-targeted
therapies in part by providing alternative proliferation and survival signals that enable
hormone independence. Modified receptors adopt alternate conformations that resist antagonism or promote agonism. SR-regulated transcription and SR-binding events have been classically studied as single receptor events using single
hormones. However, it is becoming increasingly evident that individual
steroids and SRs rarely act alone. Emerging evidence shows that coexpressed SRs crosstalk with each other in
hormone-driven
cancers, such as breast and prostate. Crosstalk between related SRs allows them to modulate signaling and transcriptional responses to noncognate
ligands. This flexibility can lead to altered genomic binding and subsequent changes in SR target gene expression. This review will discuss recent mechanistic advances in elucidating SR crosstalk and the implications for treating
hormone-driven
cancers. Understanding this crosstalk (i.e., both opposing and collaborative) is a critical step toward expanding and modernizing endocrine
therapies and will ultimately improve patient outcomes.