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Interrogating Niche-specific Nuclear and Extra-Nuclear Estrogen Receptor-alpha (ER) Signaling to Prevent ER+ Breast Cancer Progression in ER+ Bone

Award Number: R01CA299298
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/10/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Interrogating Niche-specific Nuclear and Extra-Nuclear Estrogen Receptor-alpha (ER) Signaling to Prevent ER+ Breast Cancer Progression in ER+ Bone - PROJECT SUMMARY Bone is a key ecosystem for estrogen receptor alpha-positive (ER+) breast cancer (BrC). ER+ BrC cells are bone-disseminated (b-d) prior to diagnosis; evolve in parallel with the primary tumor; can remain dormant in bone for decades; are the first site of ER+ metastatic growth in most who ultimately progress; and can seed other sites. This association of tumor ER expression with bone-specific progression suggests a possible mechanistic role for tumor ER signaling within bone, a postulate supported by our research team’s pre-clinical evidence that tumor ER signaling drives tumor-adjacent osteolysis. Yet, despite first line use of estrogen/ER targeting drugs blocking canonical (nuclear) tumor cell ER signaling, ER+ metastatic BrC remains incurable. Given the centrality of bone to ER+ BrC, to improve ER-targeted therapeutics and ER+ BrC survival, we postulate that ER signaling in its entirety within the bone microenvironment, whose varied niches are also all ER - regulated, must be elucidated and targeted. Our recent pre-clinical evidence that extranuclear (non-canonical) ER signaling, while not required for primary ER+ tumor progression, is required for progression in bone strongly supports this hypothesis. To fill this knowledge gap, we will pursue three aims. In Aim 1, we will identify tumor vs bone niche-specific and ER pathway (nuclear vs extra-nuclear)-specific, tumor-promoting effects of ER signaling using a human (hu) BrC bone metastasis (BMET) model and a combination of pharmacologic and genetic approaches, including use of treatment-resistant ER+ BrC cells with clinically important activating ESR1 mutations. Niche- and pathway-specific ER -regulated processes driving progression will be identified in Aim 1 (and Aims 2&3) by histomorphometric and geospatial profiling of niche-specific transcriptomes within the tumor/bone microenvironment, with translational significance confirmed by relevant in vitro studies. In Aim 2, because nuclear-only ER signaling is not bone anabolic and lacks the ability to promote ER+ progression in bone despite its BrC proliferative effects, we will test the postulate that bone anabolism promotes b-d ER+ BrC progression by comparing tumorigenic effects of ER ligands with those of intermittent PTH, a clinical anabolic agent whose use in breast cancer survivors is currently avoided despite a paucity of evidence, examining effects on dormant b-d ER+ BrC cells and ER+ BMET progression. In Aim 3, we will directly test our postulate that bone effects of endocrine therapies contribute to effective targeting ER+ breast cancer in bone by comparing tumorigenic effects of tissue-selective ER modulators/degraders (SERM/SERD) that are tumor antagonists with opposing bone-niche agonist vs antagonist effects, again examining both ER+ dormant cells in bone and ER+ BMET progression, including identification of bone-niche specific ER pathways driving responses. Our team is well-suited to undertake these impactful studies, which will require the use of mice for modeling since neither organoids, AI, nor bone-on-chip models are currently capable of replicating all clinically relevant cellular aspects of the tumor/bone milieu, including mapping the interactome of complex transcriptional changes driving BrC progression in this complex, non-homogeneous tissue.


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 = $545,195 )
2026	2026	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cancer Biology Research	000	1	7/10/2026	NEW	$545,195
														Subtotal = $545,195

Grand Total All Awards = $545,195

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Interrogating Niche-specific Nuclear and Extra-Nuclear Estrogen Receptor-alpha (ER) Signaling to Prevent ER+ Breast Cancer Progression in ER+ Bone

Award Number: R01CA299298

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/10/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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