Abrogating endocrine resistance by targeting ERec and PI3K in breast cancer

Antiestrogen therapies targeting estrogen receptor a (ER) signaling are a mainstay for patients with ER+ breast cancer. While many cancers exhibit resistance to antiestrogen therapies, a large body of clinical and experimental evidence indicates that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway promotes antiestrogen resistance. In addition, continued ligand-independent ER signaling in the setting of estrogen deprivation may contribute to resistance to endocrine therapy. PI3K activates several proteins which promote cell cycle progression and survival. In ER+ breast cancer cells, P13K promotes ligand-dependent and -independent ER transcriptional activity. Models of antiestrogenresistant breast cancer often remain sensitive to estrogen stimulation and P13K inhibition, suggesting that clinical trials with combinations of drugs targeting both the P13K and ER pathways are warranted. Herein, we review recent findings on the roles of P13K and ER in antiestrogen resistance, and clinical trials testing drug combinations which target both pathways. We also discuss the need for clinical investigation of ER downregulators in combination with P13K inhibitors.