Homeobox transcription factor MSX2 down-regulates ERα action to facilitate anti-estrogensensitivity in ERα+ breast cancer

Zhao, Y.; Feng, J.; Zeng, K.; Wang, A.; Sun, H.; Jin, Z.; Liu, Z.; Feng, S.; Sun, X.; Bai, Y.; He, M.; Liu, W.; Wang, M.; Yang, D.; Wang, J.; Xu, L.; Wang, C.; Wang, S.

doi:10.64898/2026.06.12.731842

bioRxiv · 10.64898/2026.06.12.731842

Homeobox transcription factor MSX2 down-regulates ERα action to facilitate anti-estrogensensitivity in ERα+ breast cancer

Zhao, Y.·Feng, J.·Zeng, K.·Wang, A.·Sun, H.·Jin, Z.·Liu, Z.·Feng, S.·Sun, X.·Bai, Y.·He, M.·Liu, W.·Wang, M.·Yang, D.·Wang, J.·Xu, L.·Wang, C.·Wang, S.

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Abstract

Breast cancer is the most common malignancy among women worldwide. Estrogen receptor (ER)-positive breast cancer is about 70% in the total breast cancer. It has variable prognosis and high recurrent risk, frequently developing resistance to endocrine therapies. Herein, we have identified that a homeobox transcription factor MSX2 downregulated in ER-positive breast cancer is correlated with the advanced grade and poor survival outcomes. Our results have demonstrated that MSX2 interacts with ER to inhibit ER-mediated transactivation. Mechanistically, MSX2 associates with HDAC1/HDAC2 to form a protein complex. MSX2 is required for recruitment of HDAC1/HDAC2 complex to estrogen response elements (EREs) region on ER downstream target genes, reducing histone H3K9ac and H3K27ac levels to inactivate gene transcription. Functionally, ectopic expression of MSX2 suppresses cell growth and enhances the sensitivity to anti-estrogen treatment in ER-positive breast cancer cells. Our results indicate that MSX2 as a novel co-repressor of ER is involved in suppression of ER-positive breast cancer progression. Restoring MSX2 protein may provide a promising strategy to overcome endocrine resistance in ER-positive breast cancer.

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Zhao, Y., Feng, J., Zeng, K., Wang, A., Sun, H., Jin, Z., Liu, Z., Feng, S., Sun, X., Bai, Y., He, M., Liu, W., Wang, M., Yang, D., Wang, J., Xu, L., Wang, C., Wang, S.. 2026-06-16. Homeobox transcription factor MSX2 down-regulates ERα action to facilitate anti-estrogensensitivity in ERα+ breast cancer. https://doi.org/10.64898/2026.06.12.731842

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