MYBL2 maintains stemness and promotes theta-mediated end joining in triple negative breast cancer

Bayley, R.; Munsey, A.; Ahmed, S.; Ward, C.; Stiby, A.; Briantseva, B.-M.; Jawanda, K.; Shaaban, A. M.; Saponaro, M.; Smith, G. C. M.; Clarke, R. B.; Davies, C.; Garcia, P.

doi:10.1101/2025.04.15.648875

bioRxiv · 10.1101/2025.04.15.648875

MYBL2 maintains stemness and promotes theta-mediated end joining in triple negative breast cancer

Bayley, R.·Munsey, A.·Ahmed, S.·Ward, C.·Stiby, A.·Briantseva, B.-M.·Jawanda, K.·Shaaban, A. M.·Saponaro, M.·Smith, G. C. M.·Clarke, R. B.·Davies, C.·Garcia, P.

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Abstract

Triple negative breast cancer (TNBC) has a poor prognosis due to limited treatment options and high metastasis risk. Breast cancer (BC) stem/progenitor cells, also known as tumour initiating cells, are a small, difficult to target population within the tumour responsible for metastasis and therapy resistance. MYBL2 overexpression is commonly linked to poor prognosis and metastasis but its role in BC stem/progenitor cells remains elusive. To determine the role of MYBL2 in BC stem/progenitor cells we generated TNBC cell lines with inducible MYBL2 downregulation. Our findings reveal that elevated MYBL2 is essential for self-renewal, DNA repair, and replication stress response in these cells and lowering MYBL2 impairs stemness and self-renewal both in vitro and in vivo. Accordingly, our functional and mechanistic analyses indicate that high-MYBL2 stem/progenitor cells exhibit increased sensitivity to Pol{theta} inhibitors which is lost upon MYBL2 downregulation due to transcriptional suppression. Combining Pol{theta} inhibitors with ATR inhibitors further enhances this sensitivity, in vitro and ex vivo. This study thus identifies Pol{theta}/ATR inhibition as a synthetic lethality strategy to eradicate BC stem/progenitor cells and underscores MYBL2 expression as a biomarker for patient stratification in this treatment.

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Bayley, R., Munsey, A., Ahmed, S., Ward, C., Stiby, A., Briantseva, B.-M., Jawanda, K., Shaaban, A. M., Saponaro, M., Smith, G. C. M., Clarke, R. B., Davies, C., Garcia, P.. 2025-04-18. MYBL2 maintains stemness and promotes theta-mediated end joining in triple negative breast cancer. https://doi.org/10.1101/2025.04.15.648875

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