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

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.

Role of EGFR and FASN in breast cancer progression

“…An interesting finding reported that protein arginine methyltransferase 1 (PRMT1) is overexpressed in all BC subtypes, and its reduction hindered cell growth by induction of DNA damage response and apoptotic pathways in BC cells. The same finding proved that PRMT1 regulates EGFR and Wnt-mediated signalling in TNBC through transcriptomic and chromatin immunoprecipitation analysis (Suresh et al 2021). PRMT1 inhibitors showed anti-tumour activity in TNBC xenograft models.…”

“…PRMT1 inhibitors showed anti-tumour activity in TNBC xenograft models. Therefore, a combinational inhibition therapy targeting EGFR and PRMT1 would be a valuable therapeutic approach for TNBC patients (Suresh et al 2021). In regards, to the combinational therapy, neratinib (HER2 inhibitor) in combination with capecitabine (pyrimidine derivatives as an anti-metabolite agent to treat BC), was approved on February 25, 2020, by U.S. FDA for the treatment of metastatic or advanced HER2+ BC patients (Xuhong et al 2019).…”