BCL11B Predetermines a Persister State in Breast Cancer That Is Reversed by TNFα [scRNA-seq]

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.

Using mouse and human breast cancer models, we found that BCL11B functions as a central regulator and 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 (TNFα) is revealed as a natural inhibitor of BCL11B and can directly reverse the emergence of chemoresistant persister cells.