Priority Research Papers:
Estrogen receptor alpha drives mTORC1 inhibitor-induced feedback activation of PI3K/AKT in ER+ breast cancer
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Abstract
Wei Yang1, Gary N. Schwartz2,5, Jonathan D. Marotti3,5, Vivian Chen1, Nicole A. Traphagen1, Jiang Gui4 and Todd W. Miller1,5
1 Department of Molecular and Systems Biology, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
2 Department of Hematology/Oncology, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
3 Department of Pathology and Laboratory Medicine, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
4 Department of Biomedical Data Sciences, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
5 Department of Comprehensive Breast Program, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
Correspondence to:
Todd W. Miller, email:
Keywords: ER; mTOR; IGF-1R; feedback; everolimus
Received: July 21, 2017 Accepted: January 09, 2018 Published: January 15, 2018
Abstract
The mTORC1 inhibitor RAD001 (everolimus) is approved for treatment of recurrent/metastatic estrogen receptor (ER)-positive breast cancer in combination with the aromatase inhibitor (AI) exemestane. The benefits of A) continued anti-estrogen therapy for anti-estrogen-resistant disease in the context of mTORC1 inhibition, and B) adjuvant everolimus in combination with anti-estrogen therapy for early-stage disease are being tested clinically, but molecular rationale remains unclear. We hypothesized that mTORC1 inhibition activates the IGF-1R/InsR/IRS-1/2 axis in an ER-dependent manner to drive PI3K/AKT and promote cancer cell survival, implicating ER in survival signaling induced by mTORC1 inhibition. Anti-estrogen treatment synergized with RAD001 to inhibit ER+ breast cancer cell growth. Inhibition of ER, IGF-1R/InsR, or IRS-1/2 suppressed AKT activation induced by mTORC1 inhibition. RAD001 primed IGF-1R/InsR for activation, which was enhanced by ER signaling. Post-menopausal patients with early-stage ER+ breast cancer were treated presurgically +/- the AI letrozole. Viable tumor fragments from surgical specimens were treated with RAD001 and/or OSI-906 ex vivo; RAD001 increased AKT activation, which was abrogated by presurgical letrozole. Letrozole decreased IGF-1R and IRS-1/2 tumor levels. These data suggest that ER drives PI3K/AKT activation in response to mTORC1 inhibition, providing molecular rationale for therapeutic combinations of anti-estrogens and mTORC1 inhibitors in endocrine-sensitive disease.
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