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, Kay Uwe Wagner

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish (US)
Article number3742
JournalNature communications
Issue number1
StatePublished - Dec 2021
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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