Targeting the mTOR Pathway for the Prevention of ER-Negative Breast Cancer
Abhijit Mazumdar, William M. Tahaney, Jamal Hill, Yun Zhang, Sumankalai Ramachandran, Jitesh D. Kawedia, Jing Qian, Alejandro Contreras, Michelle I. Savage, Lana A. Vornik, Shizuko Sei, Altaf Mohammed, Powel H. Brown
Abstract
Abstract Prevention of estrogen receptor (ER)-positive breast cancer is now possible using anti-estrogen drugs; however, this treatment is ineffective against ER-negative breast cancers. In this study, we hypothesized that inhibition of mTOR will suppress the growth of ER-negative and triple-negative breast cancers. To test the hypothesis, we used five ER-negative breast cancer models: MMTV-erbB2, C3 (1)/SV40TAg, p53-null mammary gland-transplant, p53-mutant mammary gland-transplant, and BRCA1co/co; MMTV-Cre+/+; p53+/– mouse models to determine whether the mTOR inhibitor everolimus is effective in preventing growth of ER-negative mammary tumors. Our study demonstrates that everolimus treatment significantly delays mammary tumor formation with varying degree in all five ER-negative mouse models. Everolimus treatment reduces the proliferation, with reduced phosphorylation of S6 kinase, and induces apoptosis of mammary tumor cells. In some of the p53-mutant mammary gland-transplant mice and C3 (1)/SV40Ag mice, everolimus completely prevents mammary tumor formation. Everolimus treatment also reduces proliferation of normal mammary gland cells. Our results support testing everolimus in clinical trials for the prevention of ER-negative breast cancer in women at high risk of ER-negative breast cancer. Prevention Relevance: Our results show that everolimus delays mammary tumor formation in multiple mouse models, suggesting that mTOR inhibitors will be useful for the prevention of ER-negative and triple-negative breast cancer in humans. See related Spotlight, p. 787