Thursday, December 11, 2025 12/11/2025

Mechanism of estrogen independent proliferation in ER+ breast cancer cells

Award Number: U01CA264620
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Mechanism of estrogen independent proliferation in ER+ breast cancer cells - Abstract Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for metastatic estrogen receptor positive (ER+), HER2 negative, breast cancer patients. However, the value of this combination in potentially curable earlier stage patients is variable. Our preliminary results examined the evolutionary trajectories of early stage breast cancer tumors using single cell transcriptomic profiling of serial tumor biopsies from a clinical trial of preoperative endocrine therapy alone (letrozole) or in combination with the cell cycle inhibitor ribociclib. Resistant tumors with accelerated loss of estrogen signaling show up-regulation of the JNK pathway, while those that maintain estrogen signaling during therapy show potentiation of CDK4/6 activation consistent with ERBB4 and ERK signaling up-regulation. Cell cycle reconstruction identified that tumors cells can reactivate during combination treatment, indicating stronger selection for a proliferative state. We hypothesize that resistance to CDK4/6 inhibition in earlier stage breast cancer is driven by JNK MAPK pathway stimulation and reactivation of the cell cycle through promotion of CDK6 expression or decreased cell cycle inhibitor function. In Aim 1, we will use a new mechanistic model of CDK4/6 regulation by cell cycle Inhibitors and Promoters (CIP) that couples estrogen and JNK signaling with cell cycle progression to measure the mechanisms driving cell cycle activation in a series of isogenic cell lines sensitive and resistant to CDK4/6 and endocrine inhibitors and in patient tumor cells. This analysis will reveal how distinct signaling pathways contribute to cell cycle reactivation during estrogen, CDK4/6 and JNK inhibition treatments and provide signatures of each resistant mechanism across cell types, over time and between systems. Aim 2 leverages our collection of patient tumors from the FELINE clinical trial to discover the intracellular and intratumoral resistance mechanisms driving proliferation. Fundamental resistance mechanisms will be measured in over ~300,000 patient cells from 360 tumor samples using single cell RNA sequencing data already in hand to identify core intracellular signaling states that act alone or in concert to drive proliferation. Next, the population of cells within each tumor will be analyzed to quantify intratumoral heterogeneity and how resistant populations differ in growing or shrinking tumors during drug treatment. Applying CIP to project proliferation across patient tumor cells will allow prediction of inhibitor strategies that most effectively block intracellular and intratumoral proliferation. Lastly, Aim 3 will apply a series of JNK pathway drugs with clinical potential to design and test treatment strategies that maintain durable inhibition of proliferation in ER+ cancer cells. Iterative feedback between mathematical models and patient/experimental data serves to provide a deep understanding of cell cycle regulation and mechanisms of dysregulation leading to resistance. Together, these experiments will reveal the balance between estrogen and alternative mediated JNK signaling, and their roles in resistance and provide a guide for therapeutic regimes with more durable control of cancer cell proliferation.


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: 2026 ( Subtotal = $0 )
2026	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	5	12/4/2025	NON-COMPETING CONTINUATION	$0
2026	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	5	12/5/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $670,567 )
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	5	8/27/2025	SUPPLEMENT FOR EXPANSION	$93,333
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	002	5	9/18/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	5	8/25/2025	NON-COMPETING CONTINUATION	$577,234
														Subtotal = $670,567

Issue Date FY: 2024 ( Subtotal = $696,661 )
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	003	4	8/8/2024	NON-COMPETING CONTINUATION	$519,329
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	005	4	8/12/2024	SUPPLEMENT FOR EXPANSION	$88,666
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	004	4	8/9/2024	SUPPLEMENT FOR EXPANSION	$88,666
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	006	4	9/6/2024	NON-COMPETING CONTINUATION	$0
2024	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	002	3	10/30/2023	SUPPLEMENT FOR EXPANSION	$0
2024	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	3	10/30/2023	SUPPLEMENT FOR EXPANSION	$0
2024	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	3	10/20/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $696,661

Issue Date FY: 2023 ( Subtotal = $748,881 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	003	3	8/23/2023	SUPPLEMENT FOR EXPANSION	$91,465
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	002	3	8/22/2023	SUPPLEMENT FOR EXPANSION	$91,465
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	3	8/18/2023	NON-COMPETING CONTINUATION	$565,951
2023	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	2	7/31/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $748,881

Issue Date FY: 2022 ( Subtotal = $928,701 )
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	2	8/30/2022	SUPPLEMENT FOR EXPANSION	$93,333
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	2	8/4/2022	NON-COMPETING CONTINUATION	$742,035
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	002	2	9/8/2022	SUPPLEMENT FOR EXPANSION	$93,333
														Subtotal = $928,701

Issue Date FY: 2021 ( Subtotal = $596,232 )
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	1	8/30/2021	NEW	$596,232
														Subtotal = $596,232

Grand Total All Awards = $3,641,042

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Mechanism of estrogen independent proliferation in ER+ breast cancer cells

Award Number: U01CA264620

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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