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bioRxiv · 10.64898/2026.06.09.731253

BCL11B predetermines a persister state in breast cancer that is reversed by TNFα

Qi, Z.·Gulati, G.·Kuo, A.·Sikandar, S.·Ho, W.·Qian, D.·Dirbas, F.·Newman, A.·Cai, S.·Clarke, M.
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Abstract

The frequent development of chemoresistance in cancer presents a significant clinical challenge, yet the underlying causes for heterogeneous drug responses remain largely elusive. Here, we systematically assessed the cellular differentiation status of human breast cancer cells utilizing single-cell atlases and identified a distinct population of immature basal-like cancer cells marked by BCL11B. Notably, higher levels of BCL11B+ cancer cells are significantly associated with early relapse in breast cancer patients who received chemotherapy. Functioning as a central regulator, BCL11B delineates an immature cell state that preferentially transitions to a drug-resistant persister state during treatment through multiple pre-existing and adaptive drug-resistance programs. Importantly, the cytokine tumor necrosis factor alpha (TNF) is revealed as a natural inhibitor of BCL11B and can directly reverse the emergence of chemoresistant persister cells. Therefore, we identify BCL11B as an unappreciated pre-determinant of drug response and a therapeutic target for a subset of breast cancer patients at high risk of developing chemoresistance.

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Qi, Z., Gulati, G., Kuo, A., Sikandar, S., Ho, W., Qian, D., Dirbas, F., Newman, A., Cai, S., Clarke, M.. 2026-06-11. BCL11B predetermines a persister state in breast cancer that is reversed by TNFα. https://doi.org/10.64898/2026.06.09.731253

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