4.8 Article

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

Journal

NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -

Publisher

NATURE RESEARCH
DOI: 10.1038/s41467-021-23957-5

Keywords

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Funding

  1. Public Health Service [CA022453, CA117930, CA202917, CA14876 (R01), CA58223 (P50)]
  2. METAvivor Research Foundation
  3. Cancer Research Training Program of the University of Nebraska Medical Center [CA009476]
  4. Breast Cancer Research Foundation
  5. NCI [F32CA228326]

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Claudin-low breast cancer is an aggressive subtype mainly composed of triple-negative mammary tumor cells with stem cell-like and mesenchymal features. The consistent activation of oncogenic RAS signaling and regulators of EMT play crucial roles in maintaining the cellular plasticity and characteristics of claudin-low mammary cancer cells.
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. The cellular origin and oncogenic drivers promoting claudin-low breast cancer are undefined. Here, the authors report that the consistent activation of oncogenic RAS signaling, 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.

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