Abstract
Background
Breast cancer is a molecularly heterogeneous disease composed of multiple intrinsic subtypes. Recent studies have highlighted the substantial intratumor heterogeneity of breast cancer, wherein malignant cells of distinct intrinsic subtypes co-exist within the same tumor. However, most existing subtyping methods are designed for bulk transcriptomic data and are therefore limited in their ability to resolve such intratumor heterogeneity at single-cell resolution.
Methods
We develop UBS93, a computational framework that enables robust molecular subtyping of both bulk tumor samples and individual breast cancer cells. We rigorously validate UBS93 and demonstrate its superior performance relative to existing approaches, particularly in identifying the highly aggressive Claudin-low subtype.
Results
Applying UBS93 to single-cell RNA sequencing data from human Basal-like breast cancers, we identify the co-existence of Basal-like and Claudin-low cancer cell populations within the same tumor—a form of intratumor heterogeneity previously observed in mouse models with genetically engineered RAS pathway alterations. Further analyses suggest that Claudin-low cancer cells originate from Basal-like population, with down-regulation of transcription factor ELF3 playing a pivotal role in the Basal-like/Claudin-low transition.
Conclusions
Our findings establish UBS93 as a powerful tool for breast cancer subtyping and uncover the intratumor heterogeneity in human Basal-like breast cancer.
Plain language summary
Breast cancer is not a single disease and different subtypes of cancer cells can exist within the same tumor. Most current methods used to classify breast cancer look at tumors as a whole and cannot detect differences between individual cells. In this study, we developed a computational tool called UBS93 which can classify breast cancer using data from either whole tumor or single cells. Using UBS93, we found that two aggressive subtypes can exist together within the same tumor. We also discovered that one subtype may arise from the other through changes in gene activity. These findings improve our understanding of breast cancer diversity and may help guide more precise diagnosis and treatment in the future.
Data availability
The authors declare that all data supporting the findings of this study are available within the article and its Supplementary information files or from the corresponding author upon reasonable request. The generated HCC70 scRNA-seq data are available at Zenodo57.
Code availability
The code, which can be used to reproduce the figures, is available at GitHub58.
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Acknowledgements
We thank Dr. Xiaohui Lin for helping us revise the manuscript. The research was supported by the National Natural Science Foundation of China (Fund 32370715, 82330108), the Science Fund for Distinguished Oversea Young Scholars of Shandong Province (2023HWYQ-015), the Taishan Young Scholar Program of Shandong Province (tsqn202312020), and the Cheeloo Young Scholar Program of Shandong University. The content is solely the responsibility of the authors and does not necessarily represent the official views of sponsors.
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J.L., K.L. conceived the study. J.L. performed the majority of computational analysis, Y.G., W.X.Y. performed all the experimental assays, K.L., S.Z.Z., and W.X.Y. supervised the study. S.R.Z., K.L. revised the manuscript. All authors contributed to writing, reviewing, and editing the manuscript and approved the manuscript.
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Li, J., Gao, Y., Zhang, S. et al. Intratumor heterogeneity in human basal like breast cancer is revealed by single cell molecular subtyping. Commun Med (2026). https://doi.org/10.1038/s43856-026-01548-z
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DOI: https://doi.org/10.1038/s43856-026-01548-z
