NIH grant: Interrogating Niche-specific Nuclear and Extra-Nuclear Estrogen Receptor-alpha (ER) Signaling to Prevent ER+ Breast Cancer Progression in ER+ Bone (1R01CA299298-01A1)

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NIH grant 1R01CA299298-01A1: Interrogating Niche-specific Nuclear and Extra-Nuclear Estrogen Receptor-alpha (ER) Signaling to Prevent ER+ Breast Cancer Progression in ER+ Bone
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: JANET L FUNK. Award: $545195.
Start: 2026-07-10T00:00:00.
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.

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