1. Dual Mechanisms of LYN Kinase Dysregulation Drive Aggressive Behavior in Breast Cancer Cells
- Author
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Tornillo, Giusy, Knowlson, Catherine, Kendrick, Howard, Cooke, Joe, Mirza, Hasan, Aurrekoetxea-Rodríguez, Iskander, Vivanco, Maria D M, Buckley, Niamh E, Grigoriadis, Anita, and Smalley, Matthew J
- Subjects
Adult ,LYN kinase ,Adolescent ,RNA Splicing ,Breast Neoplasms ,environment and public health ,Article ,Mice ,Young Adult ,breast cancer ,PIN1 ,Cell Movement ,c-KIT ,Cell Line, Tumor ,hemic and lymphatic diseases ,Animals ,Humans ,Neoplasm Invasiveness ,skin and connective tissue diseases ,lcsh:QH301-705.5 ,Cell Proliferation ,BRCA1 Protein ,src family kinases ,Epithelial Cells ,hemic and immune systems ,BRCA1 ,triple-negative/basal-like breast cancer ,Survival Analysis ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Isoenzymes ,NIMA-Interacting Peptidylprolyl Isomerase ,Proto-Oncogene Proteins c-kit ,enzymes and coenzymes (carbohydrates) ,HEK293 Cells ,src-Family Kinases ,lcsh:Biology (General) ,Female ,biological phenomena, cell phenomena, and immunity ,mammary cells ,ESRP1 - 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., Graphical Abstract, Highlights • LYN kinase is a downstream effector of the c-KIT receptor in normal breast cells • Loss of BRCA1 function hyperactivates LYN via prolyl isomerase 1 upregulation • The full-length LYN isoform promotes tumor cell invasion • Time to breast cancer death is shorter in tumors with a high LYNA::B isoform ratio, 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.
- Published
- 2018