The KRAS-variant and its impact on normal breast epithelial cell biology

Autor: Erina Vlashi, David K. Ann, Song-Yi Jung, Joanne B. Weidhaas, Kiana C Nguyen, Yue Qi, David Salzman, Poonam Malhotra, Ethan H Pak, Joshua King
Rok vydání: 2019
Předmět:
Zdroj: Cell death and differentiation, vol 26, iss 12
Cell Death Differ
ISSN: 1476-5403
1350-9047
DOI: 10.1038/s41418-019-0320-y
Popis: MicroRNA (miRNA)-binding site variants in 3′ untranslated regions (3′UTRs) are a novel class of germ-line, functional mutations, which are now recognized as powerful biomarkers of human cancer risk and biology. The first mutation discovered in this class is the KRAS-variant, a let-7-binding site mutation in the 3′UTR of the KRAS oncogene. The KRAS-variant predicts increased cancer risk for certain populations, is a predictive biomarker of cancer treatment response across cancer types, leads to conserved tumor biology and elevated AKT signaling in KRAS-variant patient tumors, and was recently found to predict elevated TGF-β and immunosuppression in cancer patients. Based on the functional biology of the KRAS-variant in cancer patients, here we chose to investigate altered normal cellular biology in the presence of the KRAS-variant, through interrogation of an isogenic normal breast epithelial cell line model with and without the KRAS-variant. We find that KRAS-variant normal breast epithelial cells exhibit a mesenchymal phenotype, which appears to be due to numerous molecular changes, including miRNA dysregulation and autocrine pathway alterations, including elevated TGF-β, resulting in ZEB and SNAIL upregulation. Our findings support the hypothesis that the KRAS-variant has a fundamental biological impact on normal cellular biology, that is conserved in these patients when they develop cancer.
Databáze: OpenAIRE
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