A Baylor College of Medicine-led team has uncovered how loss of tumor suppressor neurofibromin (NF1) in estrogen receptor-positive (ER+) breast cancer cells drives the cells’ preference to metastasize to the bone.
The findings, published in Cancer Letters , suggest that NF1 loss functionally links therapy resistance with increased bone metastatic potential and support investigating whether matching patient NF1 tumor status with current approved therapies can effectively reduce the incidence of bone metastasis.
“More than 70% of breast cancers are ER+ and metastasis is the main cause of death in ER+ breast cancer, reaching approximately half a million deaths globally each year,” said corresponding author Dr. Eric C. Chang , professor in the Breast Center and the Dan L Duncan Comprehensive Cancer Center at Baylor. “Having a better understanding of what promotes ER+ breast cancer cell metastasis to the bone is both clinically and biologically relevant to improving current treatments. In the current study, we investigated how loss of NF1 in ER+ breast cancer cells drives the cells to spread to the bone.”
The NF1 gene normally acts as a tumor suppressor by helping keep cell growth under control. In addition, as previous studies have shown, loss of NF1 can make primary ER+ breast cancer tumors resistant to hormone therapy, helping them grow. In the current study, NF1 loss is common in metastatic ER+ breast cancer – about 62% of ER+ patients in a metastatic breast cancer dataset had evidence of NF1 loss. This implicates NF1 loss in disease progression.
Working with animal models and cell experiments in the lab, the researchers discovered two ways that NF1 loss appears to promote bone metastasis. First, they found that NF1-depleted ER+ breast cancer cells can express genes normally active in bone cells and potently induce the development of osteoclasts – bone cells specialized in bone breakdown – and bone loss in cells cultured in the lab.
“Excessive osteoclast activity causes bone destruction, releasing growth factors stored in the bone that can further stimulate tumor growth. This creates a self-reinforcing cycle in which cancer damages bone and the damaged bone, in turn, supports cancer growth,” Chang said.
Second, NF1 loss appeared to weaken the body's immune response against cancer. “Analysis of patient samples showed that tumors with low NF1 levels had fewer active cancer-fighting CD8+ T cells and more signs of T-cell exhaustion,” Chang said. “Laboratory experiments confirmed that NF1-deficient cancer cells suppressed immune T-cell proliferation, reduced production of immune signaling molecules and made it more difficult for engineered cancer-killing T cells to destroy tumor cells.”
Together, these findings suggest that loss of NF1 allows ER+ breast cancer cells to remodel their environment in ways that favor their survival and growth. By simultaneously promoting bone destruction and suppressing anti-tumor immunity, NF1 loss creates conditions that help cancer establish and expand within the skeleton.
“Our study highlights NF1 as a potentially important biomarker for identifying patients at higher risk of bone metastasis and suggests that therapies targeting bone remodeling, immune suppression or NF1-related pathways could offer new treatment opportunities,” Chang said.
Other contributors to this work include 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 and Xiang H.-F. Zhang. The authors are affiliated with Baylor College of Medicine, DeBakey High School for Health Professions, Icahn School of Medicine at Mount Sinai – New York, Roswell Park Comprehensive Cancer Center at Buffalo, and the University of Texas Medical Branch at Galveston.
This study was supported by a CPRIT Training Award (RP210027), a CPRIT Core Facility Support Award (RP240432) and NIH grants (CA125123, OD036336, and OD038251). Further support was provided by a Breast Cancer SPORE from the NIH (P50CA186784) and the Department of Defense (grants W81XWH-21-1-0106, W81XWH-21-1-0634 and HT94252410103).
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Cancer Letters
Experimental study
Cells
NF1 loss in estrogen receptor-positive breast cancer induces osteoclast formation and immunosuppression to promote bone metastasis
29-May-2026