In estrogen receptor positive (ER+) breast cancer, an elevated mTOR activity causes resistance to conventional chemo- and hormonal therapies. Estrogen and its membrane- associated estrogen receptors are known to contribute to this abnormal mTOR activity independent of their role in transcription. However, the underlying mechanism remains unknown. Recently, arachidonic acid (AA) and its metabolites have been found to serve as key mediators for the non-genomic action of estrogen. In concert with this finding, we have observed a strong correlation between AA level and mTOR activity in tumor samples from breast cancer patients. These observations suggest a potential signaling nexus that links estrogen, AA and mTOR. This exploratory R21 project is proposed to delineate the molecular basis for this novel signaling scheme. Three lines of investigation are planned to test the hypothesis that estrogen activates mTOR through the AA metabolic cascade, including determining: 1) the role of AA metabolic cascade in estrogen-induced mTOR activation, 2) the metabolites of AA involved mTOR regulation, and 3) the mechanism by which the metabolites of AA activate mTOR. Successful completion of the proposed research will not only shed light on a novel signaling mechanism for mTOR activation but also allow further elevation of the therapeutic implication of this signaling mechanism in breast cancer treatment.

Public Health Relevance

A majority of breast cancer contains elevated levels of estrogen receptors and is referred to as ER-positive. Treatment for this type cancer includes chemotherapeutic and hormone therapies. However, resistance to these conventional therapies is often encountered. While the cause for the resistance is complex, recent studies have shown that an activated mTOR signaling activity contributes significantly to this process. Clinically, inhibition of mTOR activity has been exploited as adjunct treatment for the drug-resistant breast cancer. This research project is proposed to study the molecular mechanisms that lead to mTOR activation in ER-positive breast cancer. The results from this study will help the development of therapeutic agents for treating breast cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Strasburger, Jennifer
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Li, Jinmei; Yan, Gonghong; Liu, Sichi et al. (2017) Target of rapamycin complex 1 and Tap42-associated phosphatases are required for sensing changes in nitrogen conditions in the yeast Saccharomyces cerevisiae. Mol Microbiol 106:938-948
Yuan, Wenjie; Guo, Shuguang; Gao, Jiaoqi et al. (2017) General Control Nonderepressible 2 (GCN2) Kinase Inhibits Target of Rapamycin Complex 1 in Response to Amino Acid Starvation in Saccharomyces cerevisiae. J Biol Chem 292:2660-2669
Davis, Saralin; Wang, Juan; Zhu, Ming et al. (2016) Sec24 phosphorylation regulates autophagosome abundance during nutrient deprivation. Elife 5:
Zhong, Mingming; Zhao, Xuwen; Li, Jinmei et al. (2016) Tumor Suppressor Folliculin Regulates mTORC1 through Primary Cilia. J Biol Chem 291:11689-97
Hu, Kejin; Guo, Shuguang; Yan, Gonghong et al. (2016) Ubiquitin regulates TORC1 in yeast Saccharomyces cerevisiae. Mol Microbiol 100:303-14
Jiang, Yu (2016) Regulation of TORC1 by ubiquitin through non-covalent binding. Curr Genet 62:553-5
Dong, Wei; Zhang, Xuejing; Liu, Weijie et al. (2015) A conserved polybasic domain mediates plasma membrane targeting of Lgl and its regulation by hypoxia. J Cell Biol 211:273-86
Wang, Juan; Davis, Saralin; Menon, Shekar et al. (2015) Ypt1/Rab1 regulates Hrr25/CK1? kinase activity in ER-Golgi traffic and macroautophagy. J Cell Biol 210:273-85
Tong, Mingming; Jiang, Yu (2015) FK506-Binding Proteins and Their Diverse Functions. Curr Mol Pharmacol 9:48-65
Zheng, Yin; Jiang, Yu (2015) mTOR Inhibitors at a Glance. Mol Cell Pharmacol 7:15-20

Showing the most recent 10 out of 11 publications