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

Cell Death & Differentiation (2019) | Download Citation

Abstract

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.

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Acknowledgements

JBW was supported by a grant from the NIH (CA157749) and DA was supported by NIH grant (R01CA220693-01) for this study. The funding body had no role in the design of the study, the collection, analysis, and interpretation of the data, or in writing of the manuscript.

Author contributions

JBW contributed to the conception and design of the study; SJ, PM, KCN, DS, YQ, EHP, JK, and EV contributed to data acquisition, SJ, KCN, EV, and DA contributed to data analysis; all authors contributed to the interpretation of the results; SJ, PM, and JBW drafted the manuscript and all authors contributed to the intellectual content of the revisions; all authors approved the final version of the manuscript.

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Affiliations

  1. Department of Radiation Oncology, University of California, Los Angeles, CA, USA

    • Song-yi Jung
    • , Poonam Malhotra
    • , Kiana C. Nguyen
    • , David Salzman
    • , Ethan H. Pak
    • , Joshua King
    • , Erina Vlashi
    •  & Joanne B. Weidhaas
  2. Department of Diabetes Complications and Metabolism, City of Hope, Duarte, CA, 91010, USA

    • Yue Qi
    •  & David Ann

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Conflict of interest

JBW has founded a company that has licensed IP around the KRAS-variant from Yale University. No funds were supplied from the company for this work, nor do the findings in this manuscript impact the value of the IP owned by Yale University. The other authors declare that they have no conflict of interest.

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Correspondence to Joanne B. Weidhaas.

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DOI

https://doi.org/10.1038/s41418-019-0320-y