Estrogen Receptor-Positive Breast Cancer: Exploiting Signaling Pathways Implicated in Endocrine Resistance

Advancements in molecular profiling and endocrine therapy (ET) have led to more focused clinical attention on precision medicine. These advances have expanded our understanding of breast cancer (BC) pathogenesis and hold promising implications for the future of therapy. The estrogen receptor-alpha is a predominant endocrine regulatory protein in the breast and in estrogen-induced BC. Successful targeting of proteins and genes within estrogen receptor (ER) nuclear and nonnuclear pathways remains a clinical goal. Several classes of antiestro-genic agents are available for patients with early, advanced, or metastatic BC, including selective ER modulators, aromatase inhibitors, and a selective ER degrader. Clinical development is focused upon characterizing the efficacy and tolerability of inhibitors that target the phosphatidylinositol 3 kinase (PI3K)/akt murine thymoma viral oncogene (AKT)/mammalian target of rapamycin inhibitor (mTOR) signaling pathway or the cyclin-dependent kinase 4/6 (CDK4/6) cell cycle pathway in women with hormone receptor-positive, human epidermal growth receptor 2-negative BC who have demonstrated disease recurrence or progression. De novo and acquired resistance remain a major challenge for women with BC receiving antiestrogenic therapy. Therefore, sequential combination of targeted ET is preferred in these patients, and the ever-increasing understanding of resistance mechanisms may better inform the selection of future therapy. This review describes the intricate roles of the PI3K/AKT/mTOR and CDK4/6 pathways in intracellular signaling and the use of endocrine and endocrine-based combination therapy in BC.