Endocrine Abstracts

Steroid receptors (SR) respond to binding of their ligands with rapid signal transduction resulting from engaging extra-nuclear receptors. This occurs in addition to the conventional aspects of steroids/nuclear SR that regulate gene transcription. In breast cancer, estrogen and progesterone receptors (ER, PR) are present at the plasma membrane in addition to the nucleus. Here the receptors activate many pathways as G-protein coupled receptors, resulting in epigenetic and genetic contributions to nuclear ER action, as well as post-translational modifications of proteins, altering their functions. In breast cancer, this impacts metabolism that fosters adaptation to changing glucose availability in these highly glycolytic tumors. Signaling through ERK, PI3K-AKT-mTor and other pathways stimulates proliferation, survival, and epithelial cell migration/invasion. ER alpha and beta also exist in the mitochondria of breast cancer cell lines, where they modulate the responses to endocrine therapies, and are potential therapeutic targets in aggressive breast cancer. Activating mutations of ERalpha in endocrine resistant tumors also function through signal transduction. The importance of extra-nuclear ER in many developmental and functional aspects is established but targeting these cellular pools of receptors in malignancy is under development.