Dual Mechanisms of LYN Kinase Dysregulation Drive Aggressive Behavior in Breast Cancer Cells

Abstract

Summary: 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. : Tornillo et al. show that in aggressive breast cancers, LYN activity is deregulated by a change in patterns of splice isoform expression. In BRCA1-dysfunctional breast cancers, LYN activity is upregulated by a prolyl isomerase (PIN1) that is normally repressed by BRCA1. Keywords: BRCA1, LYN kinase, triple-negative/basal-like breast cancer, PIN1, ESRP1, c-KIT