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

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.

Citation

Song-Yi Jung, Poonam Malhotra, Kiana C Nguyen, David Salzman, Yue Qi, Ethan H Pak, Joshua King, Erina Vlashi, David Ann, Joanne B Weidhaas. The KRAS-variant and its impact on normal breast epithelial cell biology. Cell death and differentiation. 2019 Dec;26(12):2568-2576

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PMID: 30932013

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