Elucidating mechanisms of endocrine resistance in estrogen receptor-positive breast cancer

The estrogen receptor (ER) pathway is crucial in breast cancer development and progression, with endocrine therapy being an effective treatment. However, resistance to this therapy, both intrinsic and acquired, limits its efficacy. This resistance arises from various mechanisms, including deregulation of the ER pathway, alterations in cell cycle and survival signaling, and activation of escape pathways, like the EGFR/HER2 pathway. New treatments targeting both ER and growth factor receptor signaling have shown promise in preclinical models, but clinical studies suggest the need for better patient identification to maximize the benefits of these strategies. Research has identified several mechanisms underlying resistance, highlighting the complexity of ER signaling and its connections to other pathways in breast cancer cells. Two key pathways, PI3K/AKT/mTOR and cyclinD1/CDK4/6, have emerged as significant targets for therapeutic intervention in endocrine-resistant breast tumors. Ongoing clinical trials are exploring individual and combination strategies targeting these pathways, along with other potential targets, to improve treatment outcomes for ER-positive breast cancer patients.