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Non-genomic actions of estrogen in breast cancer

Award Number: R01CA100366
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/02/2004
PERIOD OF PERFORMANCE END DATE: 05/31/2017

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Non-genomic actions of estrogen in breast cancer - DESCRIPTION (provided by applicant): Traditional thinking is that nuclear ER? modulates the genes that are essential to breast cancer development. Although this is certainly true, additional actions of estrogen at locations outside the nucleus contributes to both transcriptional and non-transcriptional effects. In our initial grant period, we established important new principals governing the localization, signaling, and cell functions of ER? at the plasma membrane. Further, we published the first data implicating mitochondrial ER? in breast cancer cells, contributing to cell survival after exposure to radiation. We now propose studies to clarify important extra-nuclear ER functions in breast cancer. We identified a conserved 9 amino acid motif in ER?, ER?, and both androgen and progesterone receptors that dictates palmitoylation, resulting in membrane localization of the sex steroid receptors. We now propose to isolate and characterize the palmitoylacyltransferase (PAT) protein(s) that palmitoylate the steroid receptors, and palmitoylation-modulating proteins (e.g.-Hsp27), each resulting in membrane localization. These proteins could be therapeutic targets in breast cancer. In specific aim 2, we propose a novel basis for tamoxifen resistance involving ER? in mitochondria. Tam-sensitive MCF7 and T47D cell lines respond to Tam with strong reactive oxygen species (ROS) formation from mitochondria, triggering PKC? and JNK activation, recruitment of Bax and Bak to the mitochondria, and membrane potential decrease. This results in apoptosome formation to trigger effector caspase activation and apoptosis. In Tam-sensitive cells, Tam engages ER? in the mitochondria as an antagonist, decreasing MnSOD activity that is important to ROS generation and subsequent death signaling. In Tam-resistant MCF7 and T47D cells, Tam engages ER? in the mitochondria as an agonist, stimulating MnSOD activity that quenches ROS formation. MnSOD knockdown with siRNA reverts Tam resistant cells to sensitive cells where Tam now causes substantial apoptosis. These studies identify novel mechanisms of Tamoxifen in resistance/sensitivity, mediated differentially through mitochondrial ER?. Whether these mechanisms underlie aromatase inhibitor resistance will also be determined. In human breast cancer specimens, it is unclear whether plasma membrane ER? contributes to tumor development or outcome. We propose in the final aim to use a modified Allred score, comparing membrane and nuclear ER? expression in 300 breast tumors. We will correlate membrane and nuclear ER? Allred expression scores to many clinical parameters, including tumor type, metastasis, response to various therapies (including tamoxifen), mortality, and BRCA1 mutation status from 15 years data. The clinical significance is to understand new actions of estrogen and tamoxifen that are important to breast cancer biology, possibly targeting membrane or mitochondrial ER for preventing or treating breast cancer.


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	2014	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Biology Research	000	10	12/13/2017	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $0 )
2016	2014	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Biology Research	000	10	6/13/2016	SUPPLEMENT FOR EXPANSION	$0
2016	2013	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Biology Research	001	10	6/13/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $0 )
2015	2014	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Biology Research	000	10	6/27/2015	SUPPLEMENT FOR EXPANSION	$0
2015	2013	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Biology Research	001	10	6/27/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $33,425 )
2014	2014	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Biology Research	000	10	8/19/2014	SUPPLEMENT FOR EXPANSION	$33,425
														Subtotal = $33,425

Issue Date FY: 2013 ( Subtotal = $211,939 )
2013	2013	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Biology Research	000	10	6/7/2013	NON-COMPETING CONTINUATION	$211,939
														Subtotal = $211,939

Issue Date FY: 2012 ( Subtotal = $225,467 )
2012	2012	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Biology Research	000	9	5/21/2012	NON-COMPETING CONTINUATION	$225,467
														Subtotal = $225,467

Issue Date FY: 2011 ( Subtotal = $225,467 )
2011	2011	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Biology Research	000	8	6/1/2011	NON-COMPETING CONTINUATION	$225,467
														Subtotal = $225,467

Issue Date FY: 2010 ( Subtotal = $232,441 )
2010	2010	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Biology Research	000	7	5/10/2010	NON-COMPETING CONTINUATION	$232,441
														Subtotal = $232,441

Issue Date FY: 2009 ( Subtotal = $232,441 )
2009	2009	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Biology Research	001	6	6/9/2009	COMPETING CONTINUATION	$232,441
2009	2008	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	5	6/9/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $232,441

Issue Date FY: 2008 ( Subtotal = $217,624 )
2008	2008	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	5	3/5/2008	NON-COMPETING CONTINUATION	$217,624
														Subtotal = $217,624

Issue Date FY: 2007 ( Subtotal = $217,624 )
2007	2007	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	4	4/12/2007	NON-COMPETING CONTINUATION	$217,624
														Subtotal = $217,624

Issue Date FY: 2006 ( Subtotal = $224,124 )
2006	2006	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	3	4/18/2006	NON-COMPETING CONTINUATION	$224,124
														Subtotal = $224,124

Issue Date FY: 2005 ( Subtotal = $229,518 )
2005	2005	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	2	7/14/2005	NON-COMPETING CONTINUATION	$229,518
														Subtotal = $229,518

Issue Date FY: 2004 ( Subtotal = $258,300 )
2004	2004	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	1	8/2/2004	NEW	$258,300
														Subtotal = $258,300

Grand Total All Awards = $2,308,370

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Non-genomic actions of estrogen in breast cancer

Award Number: R01CA100366

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/02/2004

PERIOD OF PERFORMANCE END DATE: 05/31/2017

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