Oncogenic Activation of SMYD3-SHCBP1 initiates Breast Cancers Development and Coupled with Resistance to Immune Therapy

Breast cancer initiation and progression are driven by various oncogenic factors and their effects on the surrounding microenvironments. Studying BRCA1 mutant mouse models and human breast cancers, we find that BRCA1 deficiency elevates Smyd3-Shcbp1 signaling, leading to an open chromatin configuration featured with H3K4me3high/H3K9me3low and activation of Ras-MAPK oncogenic pathway in the premalignant mammary epithelium. The Smyd3-Shcbp1 signaling, which is exacerbated under the effect of estrogen-ER-alpha in premalignant mammary epithelium, shapes the tumor immunosuppressive microenvironment (TIME) and enhances tumor outgrowth associated with immune therapy resistance to alphaPD1. Finally, we show that trametinib, a potent inhibitor for MEK/MAPK, could reverse expressions of Smyd3 and Shcbp1 and that the combinatory treatment of trametinib and alphaPD1 enhances the function of the effector T cells, sensitizing the tumors with elevated Smyd3 and Shcbp1 signaling to immune checkpoint blockade (ICB). This study advances the understanding of breast tumor progression and provides a new selective strategy for breast cancer patients.