PRMT1 regulates EGFR and Wnt signaling pathways and is a promising target for combinatorial treatment of breast cancer

Suresh, S.; Huard, S.; Brisson, A.; Nemati, F.; Poulard, C.; Ye, M.; Martel, E.; Reyes, C.; Silvestre, D. C.; Meseure, D.; Nicolas, A.; Gentien, D.; Le Romancer, M.; Decaudin, D.; Roman-Roman, S.; Dubois, T.

doi:10.1101/2021.10.22.465320

bioRxiv · 10.1101/2021.10.22.465320

PRMT1 regulates EGFR and Wnt signaling pathways and is a promising target for combinatorial treatment of breast cancer

Suresh, S.·Huard, S.·Brisson, A.·Nemati, F.·Poulard, C.·Ye, M.·Martel, E.·Reyes, C.·Silvestre, D. C.·Meseure, D.·Nicolas, A.·Gentien, D.·Le Romancer, M.·Decaudin, D.·Roman-Roman, S.·Dubois, T.

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Abstract

Identifying new therapeutic strategies for triple-negative breast cancer (TNBC) patients is a priority as these patients are highly prone to relapse after chemotherapy. Here, we found that protein arginine methyltransferase 1 (PRMT1) is highly expressed in all breast cancer subtypes. Its depletion decreases cell survival by inducing DNA damage and apoptosis in various breast cancer cell lines. Transcriptomic analysis and chromatin immunoprecipitation revealed that PRMT1 regulates the epidermal growth factor receptor (EGFR) and the Wnt signaling pathways, reported to be activated in TNBC. The enzymatic activity of PRMT1 is also required to stimulate the canonical Wnt pathway. Recently developed type I PRMT inhibitors decrease breast cancer cell proliferation and show anti-tumor activity in a TNBC xenograft model. These inhibitors display synergistic interactions with some chemotherapies used to treat TNBC patients, as well as the EGFR inhibitor, erlotinib. Therefore, targeting PRMT1 in combination with drugs used in the clinic may improve current treatments for TNBC patients. SignificanceThis study highlights the requirement of PRMT1 for breast cancer cell survival and demonstrates the potential of targeting type I PRMTs in combination with chemotherapies in triple-negative breast cancer.

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Suresh, S., Huard, S., Brisson, A., Nemati, F., Poulard, C., Ye, M., Martel, E., Reyes, C., Silvestre, D. C., Meseure, D., Nicolas, A., Gentien, D., Le Romancer, M., Decaudin, D., Roman-Roman, S., Dubois, T.. 2021-10-23. PRMT1 regulates EGFR and Wnt signaling pathways and is a promising target for combinatorial treatment of breast cancer. https://doi.org/10.1101/2021.10.22.465320

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