Dual mechanisms of LYN kinase dysregulation drive aggressive behaviour in breast cancer cells

The SRC-family kinase LYN is highly expressed in triple-negative/basal-like breast cancer (TNBC) and in the cell-of-origin of these tumors, c-KIT-positive luminal progenitors. Here we demonstrate LYN is a downstream effector of c-KIT in normal mammary cells and protective of apoptosis upon genotoxic stress. LYN activity is modulated by PIN1, a prolyl isomerase, and in BRCA1-mutant TNBC PIN1 upregulation activates LYN independently of c-KIT. Furthermore, the full-length LYN splice isoform (as opposed to the Δaa25-45 variant) drives migration and invasion of aggressive TNBC cells, while the ratio of splice variants is informative for breast cancer-specific survival across all breast cancers. Thus, dual mechanisms – uncoupling from upstream signals and splice isoform ratios – drive the activity of LYN in aggressive breast cancers.