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The pro-metastatic role of androgen receptor in estrogen receptor mutated breast cancer

Award Number: R01CA279108
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/08/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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The pro-metastatic role of androgen receptor in estrogen receptor mutated breast cancer - The five-year survival rate for metastatic breast cancer (MBC) remains less than 50% and nearly all patients eventually succumb to the disease; therefore, understanding pro-metastatic mechanisms for adjuvant therapy resistant breast cancer (BC) remains a critical unmet need in the field. Our long-term goal is to elucidate adaptive changes that enable BC cells to persist and recur as metastatic disease and to reveal new therapeutic vulnerabilities. The standard of care adjuvant therapy for estrogen receptor alpha positive (ER+) BC in postmenopausal women (the most common form of the disease) is estrogen (E2)-deprivation achieved through aromatase inhibitors (AI). AI therapy blocks conversion of androgens to E2, effectively decreasing E2 production, but increases circulating and intra-tumoral androgens. The Richer laboratory has published extensively on mechanisms by which androgen receptors (AR) interact with driving pathways in the three main BC subtypes. Recently, the Yu laboratory independently discovered that AR supports tumor cell survival under cellular stress incurred by E2-deprivation (simulating AI therapy) and reactive oxygen species (ROS) incurred by anchorage independence and may thereby facilitate relapse as metastatic disease. Indeed, the two labs independently discovered that AR is further elevated in BC cells with ER hot spot mutations that are exclusively detectable in MBCs following resistance to AI therapy. Since surviving E2-deprivation therapy and anchorage independence is critical to metastatic progression of ER+ BC, understanding the role of AR in these conditions is highly relevant for MBC. It is known that a critical barrier for circulating tumor cell (CTC) survival during metastasis is to overcome the high level of ROS in anchorage independent conditions. These data led to our hypothesis that AR promotes reduction of ROS and CTC survival thereby promotes metastasis. We combine expertise of AR signaling (Richer) and metastasis (Yu) and use mutant ER BC cell lines, patient derived CTC lines, patient derived xenografts (PDX), and murine syngeneic models to test the following aims. We will evaluate the role and mechanisms of AR upregulation during estrogen deprivation and anchorage-independent survival of ER mutant BC cells, by examining the ROS levels impacted by AR activity, AR binding profile and downstream targets in vitro, as well as the mechanism for AR upregulation in anchorage independent condition (Aim 1). We will examine the contribution and mechanisms of AR mediated pro-metastatic signals in vivo, via evaluating the impact of AR inhibition on metastatic potential in mutant ER cells, the AR levels in CTCs and metastasis, as well as the binding profiles of AR and the role of its downstream targets in promoting metastases (Aim 2). This application is aimed to determine how AR supports ER mutant BC to resist stresses incurred during metastatic progression, with the goal of devising better therapeutic strategies to reduce mortality from MBC.


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 = $558,043 )
2026	2026	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Biology Research	000	3	12/22/2025	NON-COMPETING CONTINUATION	$558,043
														Subtotal = $558,043

Issue Date FY: 2025 ( Subtotal = $630,810 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Biology Research	000	2	1/27/2025	NON-COMPETING CONTINUATION	$567,729
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Biology Research	001	2	5/28/2025	NON-COMPETING CONTINUATION	$63,081
														Subtotal = $630,810

Issue Date FY: 2024 ( Subtotal = $656,397 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Biology Research	000	1	1/8/2024	NEW	$656,397
														Subtotal = $656,397

Grand Total All Awards = $1,845,250

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The pro-metastatic role of androgen receptor in estrogen receptor mutated breast cancer

Award Number: R01CA279108

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/08/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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