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

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 and Kay-Uwe Wagner ()
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Patrick D. Rädler: Barbara Ann Karmanos Cancer Institute
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

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23957-5

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