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.
Keywords: PI3K, breast cancer, antiestrogen, aromatase, fulvestrant, tamoxifen, estrogen receptor
Citation: Fox EM, Arteaga CL and Miller TW (2012) Abrogating endocrine resistance by targeting ERα and PI3K in breast cancer. Front. Oncol. 2:145. doi: 10.3389/fonc.2012.00145
Received: 21 August 2012; Paper pending published: 18 September 2012;
Accepted: 30 September 2012; Published online: 16 October 2012.
Edited by:Alexandre Arcaro, University of Bern, Switzerland
Reviewed by:Keisuke Ito, Harvard Medical School, USA
Copyright: © 2012 Fox, Arteaga and Miller. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Todd W. Miller, Dartmouth–Hitchcock Medical Center, One Medical Center Drive, HB-7936, Lebanon, NH 03756, USA. e-mail: email@example.com