SMYD3-SHCBP1 Oncogenic Axis Drives Pregnancy-Associated Breast Cancer Progression induced by BRCA1 deficiency

Pregnancy has a dual role in serving as a risk factor for pregnancy-associated breast cancer (PABC) and as a long-term protection factor against breast cancer, yet the underlying mechanism is unclear. In this study, we find BRCA1 plays a protective role in suppressing PABC and BRCA1 deficiency triggers open chromatin featured with elevated H3K4me3 and increased transcriptional activity of sub-set of oncogenes during pregnancy. The analysis reveals that Smyd3 is further induced by both ERa and Brca1 deficiency which leads to PABC progression. We demonstrate that oncogenic signal of Ras-MAPK induced by elevated Smyd3-Shcbp1 exists in the premalignant mammary glands and exacerbate oncogenic signals in premalignant cells during pregnancy in Brca1 mutant mice.