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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA169186-01A1
Application #
8509187
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Strasburger, Jennifer
Project Start
2013-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$199,013
Indirect Cost
$68,513
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Zou, Huafei; Lai, Yumei; Zhao, Xuwen et al. (2013) Regulation of mammalian target of rapamycin complex 1 by Bcl-2 and Bcl-XL proteins. J Biol Chem 288:28824-30