Molecular mechanisms of endocrine resistance

Estrogen receptor-positive (ER+) breast cancer is the most common subtype of breast cancer. Endocrine therapy targeting the ER pathway is effective, yet endocrine resistance is prevalent and remains a clinical challenge. The mechanisms underlying endocrine resistance are multifaceted and are likely to continue evolving over time in response to various endocrine regimens. The expression of ER in most endocrine-resistant tumors underscores ER’s continuing role, although altered, often via crosstalk with hyperactive growth factor receptor and intracellular kinase signaling pathways. These interactions can alter ER’s sensitivity to various endocrine agents and lead to the activation of distinct transcriptional programs that provide proliferation and survival signaling to escape endocrine therapy. Additional molecular determinants inflicting ER transcriptional reprogramming to promote endocrine resistance include alterations of ER coregulators and pioneer factors, and genetic aberrations of ER itself. Recent advances in our understanding of the mechanisms of endocrine resistance, mostly provided by large-scale sequencing studies, further establish the roles of epigenetic alterations, the DNA damage response, the tumor microenvironment, and the immune response in promoting the endocrine-resistant ER+ disease. Progress has been made in translating several of these findings into effective new targeted therapies, such as inhibitors targeting the key signaling node mTOR and the cyclin-dependent kinases CDK4 and CDK6. However, considerable challenges remain in (1) developing new tailored treatment strategies with enhanced efficacy and reduced toxicity, (2) improving the patient selection approaches for these new treatments, and (3) advancing our understanding of how to harness the recent developments in immunotherapy to support other therapeutic strategies to prevent or overcome endocrine resistance and disease progression. It is our hope that continuing translational research will unveil more converging targets and pathways associated with altered ER transcriptional reprogramming, which can be therapeutically exploited to prevent and/or reverse endocrine resistance