Oncogenic activation of SMYD3-SHCBP1 promotes breast cancer development and is coupled with resistance to immune therapy.

Breast cancer initiation and progression are driven by various oncogenic factors and their effects on the surrounding microenvironments. Through integrative analysis of ChIP-sequencing and RNA-sequencing with fast proliferating mammary epithelial cells from pregnant Brca1^MKO and wild type (WT) mice, we found that elevated Smyd3-Shcbp1 signaling is featured with activation of the Ras-MAPK pathway and increased transcription activity in both premalignant mammary epithelium and tumor cells. Smyd3-Shcbp1 signaling shapes the tumor immunosuppressive microenvironment (TIME) and is associated with immune therapy resistance to PD1 antibody treatment. Trametinib, a potent inhibitor of MEK/MAPK, could reverse the expression of Smyd3 and Shcbp1 in both Brca1 mutant and WT tumor bearing mice. We further demonstrated that the combinatory treatment of trametinib together with PD1 antibody enhances the function of effector T cells, sensitizing tumors with elevated Smyd3 and Shcbp1 signaling to αPD1 treatment. This study advances the understanding of breast tumor progression and provides a new selective strategy for breast cancer patients.