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Discovery and Characterization of an Estrogen Responsive Long Non-Coding RNA

Award Number: F30CA200328
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/01/2016
PERIOD OF PERFORMANCE END DATE: 05/31/2017

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Discovery and Characterization of an Estrogen Responsive Long Non-Coding RNA - DESCRIPTION (provided by applicant): Breast cancer is one of the most prevalent cancers and is a complex and heterogeneous group of diseases that arises in mammary glands due to a variety of somatic mutations and epigenetic changes that characterize individual tumors. The estrogen receptor (ER), particularly ER-α, is a well-studied driver of breast cancer and serves as both a strong prognostic marker and a predominant therapeutic target. In fact over 60% of all breast cancers are ER positive. ER functions as a ligand-dependent transcription factor, binding genomic estrogen response elements to either activate or repress the transcription of target genes. Most studies of ER-positive breast tumors and cell lines have focused on proteins regulated by ER as potential modulators of tumor progression, largely overlooking the possible role of non-coding RNAs in tumor formation. Long noncoding RNAs (lncRNAs) have emerged as an important class of genes involved in many cellular processes and have been implicated in biological, developmental, and pathological processes. Several human lncRNAs have already been shown to be integral players in cancer progression, including HOTAIR in breast cancer and SCHLAP1 and PCAT1 in prostate cancer. However, lncRNAs have not yet been shown to play a role in mediating ER-driven breast cancer. Investigating the role of lncRNAs in ER driven cancers is an exciting avenue for further understanding the mechanisms of breast cancer progression. Our preliminary data have identified an intriguing ER associated lncRNA, BRCAT431, that is differentially expressed in breast cancer, transcriptionally responsive to estrogen stimulation, confers transformative phenotype in breast cancer cell lines, and binds the protein hnRNPL. Preclinical, clinical, and mechanistic investigation of this lncRNA is outlined in this proposal. Specific Aim 1: Characterize preclinical and clinical phenotype of BRCAT431. We will investigate the oncogenic potential of in in vivo mouse xenograft studies. We will also assess the association of BRCAT431 with poor clinical outcomes through interrogation of clinical datasets bearing expression data for the lncRNA. Specific Aim 2: Functional characterization of BRCAT431 and hnRNPL interaction. We have shown that the two molecules physically interact and aim to characterize the functionality of this interaction. We propose to identify overlap in the genes whose expression is regulated by hnRNPL and BRCAT431. Additionally we will localize and delete the binding site of hnRNPL on BRCAT431, and subsequently overexpress mutant BRCAT431 lacking hnRNPL binding to assess the function of the binding interaction. Specific Aim 3: Assess the affect of BRCAT431 on the RNA binding profile of hnRNPL. Given that hnRNPL is a known regulator of RNA splicing and stability, in order to further investigate the functional relationship between BRCAT431 and hnRNPL, we will perform CLIP-seq with and without BRCAT431 knockdown to characterize the effect of BRCAT431 on the RNA binding profile of hnRNPL.


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: 2020 ( Subtotal = -$39,957 )
2020	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Research Manpower	000	2	3/31/2020	NON-COMPETING CONTINUATION	-$39,957
														Subtotal = -$39,957

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Research Manpower	000	2	3/28/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $44,044 )
2017	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Research Manpower	002	2	7/27/2017	NON-COMPETING CONTINUATION	$468
2017	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Research Manpower	000	2	4/27/2017	NON-COMPETING CONTINUATION	$43,576
2017	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Research Manpower	001	2	6/30/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $44,044

Issue Date FY: 2016 ( Subtotal = $34,404 )
2016	2016	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Research Manpower	000	1	3/28/2016	NEW	$34,404
2016	2016	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Research Manpower	001	1	3/28/2016	NEW	$0
														Subtotal = $34,404

Grand Total All Awards = $38,491

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Discovery and Characterization of an Estrogen Responsive Long Non-Coding RNA

Award Number: F30CA200328

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/01/2016

PERIOD OF PERFORMANCE END DATE: 05/31/2017

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