Abstract
Antiestrogen therapies targeting estrogen receptor α (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, PI3K promotes ligand-dependent and -independent ER transcriptional activity. Models of antiestrogen-resistant breast cancer often remain sensitive to estrogen stimulation and PI3K inhibition, suggesting that clinical trials with combinations of drugs targeting both the PI3K and ER pathways are warranted. Herein, we review recent findings on the roles of PI3K 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 PI3K inhibitors.
Highlights
At least 75% of breast cancers express estrogen receptor α (ER) and/or progesterone receptor (PR), which are tumor biomarkers of estrogen dependence
A large body of experimental and clinical evidence suggests that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway, the most frequently mutated pathway in breast cancer, promotes antiestrogen resistance
PI3K is commonly activated by growth factor receptor tyrosine kinases and G-protein-coupled receptors in breast cancer cells
Summary
At least 75% of breast cancers express estrogen receptor α (ER) and/or progesterone receptor (PR), which are tumor biomarkers of estrogen dependence. RATIONALE FOR COMBINED TARGETING OF THE ER AND PI3K PATHWAYS We and others identified a requirement for PI3K in the estrogenindependent growth of long-term estrogen-deprived (LTED) ER+ breast cancer cells, which mirror clinical resistance to AIs (Sabnis et al, 2007; Crowder et al, 2009; Miller et al, 2010).
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