期刊
CELL REPORTS
卷 25, 期 13, 页码 3674-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2018.11.103
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资金
- Breast Cancer Now [2012MayPR076, 2012MaySF122, 2013NovPhD184]
- Breast Cancer Research Aid
- Wales Cancer Research Centre
- Cancer Research UK [CRUK/A15938]
- European Cancer Stem Cell Research Institute
- Cardiff University
- Cancer Research UK
- MINECO/FEDER, EU [SAF2017/84934/R]
- Centro Excelencia Severo Ochoa-Agencia Estatal de Investigacion [SEV-2016-0644]
- Breast Cancer Now
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 Delta aa25-45 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.
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