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The role of the mTOR signaling pathway in ER-positive breast cancer

Award Number: R15CA151112
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2010
PERIOD OF PERFORMANCE END DATE: 06/30/2017

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The role of the mTOR signaling pathway in ER-positive breast cancer - DESCRIPTION (provided by applicant): Background: Clinically, up to 60% of breast cancers are ER-positive, indicative of estrogen dependence for cancer cell growth. ER-positive breast cancers can be targeted therapeutically by antiestrogens (such as tamoxifen) or aromatase inhibitors (AIs). However, only about half of ER-positive breast cancers respond to endocrine treatments, and resistance frequently develops. An important clinical strategy is to use a combination therapy approach with inhibitors of other pathways in order to enhance the efficacy of endocrine therapy, and suppress the development or induce reversal of resistance. One of the most important pathways in regulating cellular growth and proliferation is the mammalian Target of Rapamycin Complex 1 (mTORC1). Inhibition of the mTORC1 pathway in combination with endocrine therapy has provided encouraging results in early clinical trials. Although great strides have been made in understanding the mechanisms of endocrine therapy sensitivity and emergence of resistance, the details are not fully understood. Objective/hypothesis: Our preliminary studies suggest that a co-regulatory relationship exists between the ER? and mTOR pathways, promoting breast cancer cell proliferation, specifically through estrogenic upregulation of a key mTOR effector, S6 Kinase 1 (S6K1, encoded by the RPS6KB1 gene), and mTORC1- mediated phosphorylation of ER? and 14-3-3?, and a novel protein SPATS2. Therefore, we propose to study the mechanistic, therapeutic and prognostic aspects of the relationship between mTORC1/S6K1 and ER pathways underlying disease progression and therapeutic resistance in breast cancer. Specific aims: We propose to investigate three distinct connections between the mTORC1 and ER pathways. We seek to (1) study mTORC1-mediated phosphorylation of 14-3-3? and SPATS2; (2) elucidate the mechanism of estrogenic expression of RPS6KB1; (3) define the role of mTORC1 signaling in ER? phosphorylation and activation. Study design: We will use Chromatin Immunoprecipitation (ChIP) to perform a comprehensive analysis of direct ER? binding to S6K1 promoter regions, and functional interactions with other transcription factors, such as GATA-3 and ERR?. To address the mode of mTOR-mediated phosphorylation of ER?, and the role of S6K1 target proteins, we will employ biochemical and cell-based measurements of kinase activity, and reporter assays for measurements of ER? transcriptional activity. Finally, we will use pharmacological and RNAi- mediated inhibition of these pathways to assess the phenotypic effects of these proteins on endocrine resistance. We will investigate changes in proliferative rates, growth, survival and apoptosis. Cancer relevance: Our proposal focuses on investigating the molecular mechanism by which ER cooperates with mTORC1 in regulating development and progression of cancer. Specifically, we would determine how this relationship affects sensitivity to endocrine therapy and development of resistance. The long-term goal is to improve therapeutic regiments for breast cancer patients by targeting patients most likely to benefit from a particular drug combination.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2013	YESHIVA UNIVERSITY	500 W 185TH ST	NEW YORK	NY	10033	NEW YORK	USA	Cancer Biology Research	000	2	11/20/2017	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $542,286 )
2013	2013	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cancer Biology Research	001	2	6/14/2013	COMPETING CONTINUATION	$500,536
2013	2013	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cancer Biology Research	002	2	9/10/2013	COMPETING CONTINUATION	$41,750
2013	2010	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Trans-NIH Recovery Act Research Support	000	1	6/10/2013	NEW	$0
														Subtotal = $542,286

Issue Date FY: 2010 ( Subtotal = $408,400 )
2010	2010	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Trans-NIH Recovery Act Research Support	001	1	6/22/2010	NEW	$0
2010	2010	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Trans-NIH Recovery Act Research Support	000	1	5/30/2010	NEW	$408,400
														Subtotal = $408,400

Grand Total All Awards = $950,686

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The role of the mTOR signaling pathway in ER-positive breast cancer

Award Number: R15CA151112

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2010

PERIOD OF PERFORMANCE END DATE: 06/30/2017

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