Mast cell activation induced by tamoxifen citrate via MRGPRX2 plays a potential adverse role in breast cancer treatment.

Breast cancer is the most common malignant tumor endangering women's life and health. Tamoxifen citrate (TAM) is the first-line drug of adjuvant endocrine therapy for estrogen receptor-positive (ER⁺) breast cancer patients. Some sporadic cases have described rare adverse reactions of TAM with potentially life-threatening dermatological manifestations, which were associated with skin allergy. Mas related G protein-coupled receptor X2 (MRGPRX2) on human mast cells is the key target for skin allergy. We aimed to investigate the mechanism of TAM-induced allergic reactions and their potential effects on TAM treatment for breast cancer. In our study, TAM can specifically bind with MRGPRX2, which was mainly driven by hydrophobic force. TAM formed hydrogen bonds with TRP243, TRP248, and GLU164 residues in MRGPRX2. TAM induced calcium mobilization and degranulation of mast cells via MRGPRX2. Besides, TAM induced passive cutaneous anaphylaxis and active systemic anaphylaxis in C57BL/6 mice. The release of β-hexosaminidase, histamine, tumor necrosis factor-α, monocyte chemoattractant protein 1, and interleukin-8 were increased by TAM in vitro and in vivo. Furthermore, we found that MCF-7 and T-47D breast cancer cells can recruit mast cells to adjacent cancerous tissues. Besides, mast cell activation induced by TAM via MRGPRX2 significantly promoted the proliferation and migration of MCF-7 and T-47D cells, which can be effectively reversed by mast cell membrane stabilizer clarithromycin and MRGPRX2 silencing. This study proposed an anti-allergic therapeutic strategy for breast cancer treatment with TAM, while also the potential of MRGPRX2 as an adjunctive target.