Residual Breast Cancer Cells Co-opt SOX5-driven Endochondral Ossification to Maintain Dormancy
Amulya Sreekumar1,2, Eric Blankemeyer3, Christopher J Sterner1,2
1Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, PA 19104, USA.
Biorxiv : the Preprint Server for Biology
|July 14, 2025
Summary
Transcription factors SOX5/6 regulate breast cancer recurrence. SOX5 promotes dormancy by inducing endochondral ossification, preventing cancer relapse and improving survival.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Recurrent breast cancer is a major cause of cancer mortality.
- Mechanisms of therapy-resistant residual tumor cells (RTCs) and recurrence remain poorly understood.
Purpose of the Study:
- To identify molecular regulators of breast cancer recurrence and dormancy.
- To investigate the role of SOX5/6 transcription factors in RTC dormancy and recurrence.
Main Methods:
- CRISPR-Cas9 screening was employed to identify regulators of tumor recurrence.
- 18F]NaF-PET imaging was used to confirm endochondral ossification.
- Gene expression analysis was performed on patient samples.
Main Results:
- Loss of SOX5 accelerated breast cancer recurrence and dormancy escape.
- SOX5 induced a cartilage-dependent bone development program (endochondral ossification) in dormant RTCs.
- Osteochondrogenic gene expression in patients predicted improved recurrence-free survival.
Conclusions:
- SOX5-dependent mesodermal transdifferentiation is an adaptive mechanism preventing breast cancer recurrence.
- Reinforcing tumor cell dormancy via SOX5 may be a therapeutic strategy against recurrence.
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