NF1 Loss in Estrogen Receptor-Positive Breast Cancer Induces Osteoclast Formation and Immunosuppression to Promote Bone Metastasis

Authors

• Zifan Zhao
• Ze-Yi Zheng
• Jonathan T Lei
• Matthew J Baik
• Yi-Hsuan Wu
• Lauren K Somes
• Andres F Mosquera Paternina
• Omar A Harb
• Owen A Chang
• Fengshuo Liu
• Matthew V Holt
• Junkai Wang
• Igor Bado
• Hai Wang
• George Miles
• Zbigniew Gugala
• Meenakshi Anurag
• Ahmed Elkhanany
• Yi Li
• Valentina Hoyos
• Xiang H-F Zhang
• Eric C Chang

Language

English

Publication Date

9-1-2026

Journal

Cancer Letters

DOI

10.1016/j.canlet.2026.218636

PMID

42217562

PMCID

PMC13418278

PubMedCentral® Posted Date

7-30-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Estrogen receptor-positive (ER+) breast cancer exhibits a marked propensity for skeletal metastasis; however, the molecular drivers of bone colonization remain incompletely defined. We investigated the tumor suppressor neurofibromin (NF1), a dual repressor for RAS and ER signaling, whose inactivation promotes endocrine therapy (ET) resistance and is associated with inferior relapse-free survival. NF1 copy number loss was detected in 62% of ER+ patients who subsequently developed metastases and was associated with an increased likelihood of bone metastases at initial diagnosis. In mouse xenograft models, NF1-depleted ER+ breast cancer cells demonstrated enhanced dissemination to skeletal sites following surgical resection of primary tumors. Furthermore, after intra-iliac injection, NF1-depleted cells generated significantly greater tumor burden in bone. Transcriptomic profiling revealed enrichment of bone-related gene signatures in NF1-depleted ER+ breast cancer cells, which more potently induced osteoclast differentiation and bone loss in co-culture systems. In parallel, low NF1 expression correlated with repressed T cell functional states in primary breast tumors and bone metastases. Consistent with these clinical observations, NF1-depleted ER+ breast cancer cells more effectively inhibited proliferation, interferon-γ secretion, and cytotoxicity of human primary CD8+ T cells. Collectively, these findings identify NF1 inactivation as a key driver of bone metastasis in a substantial subset of ER+ breast cancers. By amplifying the osteolytic “vicious cycle” and promoting immune evasion, NF1 loss remodels the microenvironment to favor tumor expansion. These results further suggest that NF1 loss functionally links therapy resistance with increased skeletal metastatic potential.

Keywords

Humans, Female, Animals, Breast Neoplasms, Osteoclasts, Neurofibromin 1, Bone Neoplasms, Receptors, Estrogen, Mice, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Coculture Techniques, RAS, transcriptional co-repressor, estrogen response, steroid hormone nuclear receptor, T cell exhaustion, T cell infiltration, cytotoxicity, osteogenesis, osteoporosis

Published Open-Access

yes

Recommended Citation

Zhao, Zifan; Zheng, Ze-Yi; Lei, Jonathan T; et al., "NF1 Loss in Estrogen Receptor-Positive Breast Cancer Induces Osteoclast Formation and Immunosuppression to Promote Bone Metastasis" (2026). Faculty, Staff and Students Publications. 7966.
https://digitalcommons.library.tmc.edu/baylor_docs/7966