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Cytoplasmic cyclin E is an early event for progression to invasive breast cancer

Award Number: R01CA223772
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2018
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Cytoplasmic cyclin E is an early event for progression to invasive breast cancer - Project Summary Cyclin E, a key regulatory protein controlling the G1 to S phase transition in mammalian cells, is post- translationally modified by neutrophil elastase mediated proteolytic cleavage to generate the low molecular weight isoforms of cyclin E (LMW-E) that are detected in many cancer types. Our laboratory has elucidated several distinct oncological attributes of LMW-E versus full length cyclin E (EL) in breast cancer, using in vitro and in vivo model systems. In this application, using a robust inducible murine transgenic model of LMW-E mediated tumorigenesis, we have mapped some of the early events in the pre-neoplastic mammary gland that gives rise to aggressive tumors with high metastatic potential. These LMW-E oncogenic events permit the induction of sustained tumorigenesis even in the absence of LMW-E expression. These events include induction of DNA damage, upregulation of several genes involved in unregulated DNA replication and G2/M transition, and specific mutations in genes, such as ALK, that is readily targetable. These preliminary results have led to the following three testable hypotheses: (1) expression of LMW-E early in the pre-invasive breast cancer (i.e. ductal carcinoma in situ) results in induction of genomic alteration leading to an invasive carcinoma, (2) LMW-E in a cyclin E knockout model will result in a more aggressive phenotype than overexpression of EL, resulting in increased genomic instability, centrosome amplification and transformability in hMECs, (3) Inhibition of ALK, a secondary oncogenic event to LMW-E induction, early in the neoplastic process can inhibit tumorigenesis and also be used as a target for the treatment of triple negative breast cancers (TNBC) expressing LMW-E. The following aims are designed to test each aspect of these 3 hypotheses: Aim 1:Examine the role of cytoplasmic cyclin E in differentiating indolent versus high-risk ductal carcinoma in situ (DCIS). Aim 2: Investigate the mechanism of LMW-E mediated DNA damage response and centrosome amplification in the absence of endogenous cyclin E in somatic hMEC models. Aim 3: Investigate the role of ALK as a mediator of LMW-E mediated mammary tumorigenesis and as a therapeutic target in TNBC. These studies have the potential to identify LMW-E-induced early oncogenic events and provide the rationale to use LMW-E as a biomarker to identify the DCIS cases which are at high risk for developing invasive cancer. Our studies will show if ALK can be a viable target for the LMW-E overexpressing TNBC patients. Since there are already several ALK inhibitors, which have undergone Phase I-III clinical trials in malignancies other than breast, the translational of these pre-clinical studies to TNBC patients could occur readily.


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: 2025 ( Subtotal = $0 )
2025	2023	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	6	12/23/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $386,160 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	6	1/26/2023	NON-COMPETING CONTINUATION	$386,160
														Subtotal = $386,160

Issue Date FY: 2022 ( Subtotal = $386,159 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	1/13/2022	NON-COMPETING CONTINUATION	$354,637
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	5	5/19/2022	NON-COMPETING CONTINUATION	$31,522
														Subtotal = $386,159

Issue Date FY: 2021 ( Subtotal = $394,040 )
2021	2021	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	4	2/1/2021	NON-COMPETING CONTINUATION	$394,040
														Subtotal = $394,040

Issue Date FY: 2020 ( Subtotal = $1 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	2/24/2020	NON-COMPETING CONTINUATION	$1
														Subtotal = $1

Issue Date FY: 2019 ( Subtotal = $537,419 )
2019	2019	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	1/31/2019	NON-COMPETING CONTINUATION	$537,419
														Subtotal = $537,419

Issue Date FY: 2018 ( Subtotal = $554,040 )
2018	2018	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	1/25/2018	NEW	$394,040
2018	2018	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	1	9/19/2018	SUPPLEMENT FOR EXPANSION	$160,000
														Subtotal = $554,040

Grand Total All Awards = $2,257,819

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Cytoplasmic cyclin E is an early event for progression to invasive breast cancer

Award Number: R01CA223772

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2018

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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