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Highly metastatic claudin-low mammary cancers can originate from luminal epithelial cells

Author

Listed:
  • Patrick D. Rädler

    (Barbara Ann Karmanos Cancer Institute
    University of Nebraska Medical Center)

  • Barbara L. Wehde

    (University of Nebraska Medical Center)

  • Aleata A. Triplett

    (University of Nebraska Medical Center)

  • Hridaya Shrestha

    (Barbara Ann Karmanos Cancer Institute)

  • Jonathan H. Shepherd

    (University of North Carolina at Chapel Hill)

  • Adam D. Pfefferle

    (University of North Carolina at Chapel Hill)

  • Hallgeir Rui

    (Medical College of Wisconsin)

  • Robert D. Cardiff

    (University of California)

  • Charles M. Perou

    (University of North Carolina at Chapel Hill)

  • Kay-Uwe Wagner

    (Barbara Ann Karmanos Cancer Institute)

Abstract

Claudin-low breast cancer represents an aggressive molecular subtype that is comprised of mostly triple-negative mammary tumor cells that possess stem cell-like and mesenchymal features. Little is known about the cellular origin and oncogenic drivers that promote claudin-low breast cancer. In this study, we show that persistent oncogenic RAS signaling causes highly metastatic triple-negative mammary tumors in mice. More importantly, the activation of endogenous mutant KRAS and expression of exogenous KRAS specifically in luminal epithelial cells in a continuous and differentiation stage-independent manner induces preneoplastic lesions that evolve into basal-like and claudin-low mammary cancers. Further investigations demonstrate that the continuous signaling of oncogenic RAS, as well as regulators of EMT, play a crucial role in the cellular plasticity and maintenance of the mesenchymal and stem cell characteristics of claudin-low mammary cancer cells.

Suggested Citation

  • Patrick D. Rädler & Barbara L. Wehde & Aleata A. Triplett & Hridaya Shrestha & Jonathan H. Shepherd & Adam D. Pfefferle & Hallgeir Rui & Robert D. Cardiff & Charles M. Perou & Kay-Uwe Wagner, 2021. "Highly metastatic claudin-low mammary cancers can originate from luminal epithelial cells," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23957-5
    DOI: 10.1038/s41467-021-23957-5
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