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

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 3742 (06 18 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34145248 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Claudins
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Cell Differentiation
• Cell Line, Tumor
• Claudins (metabolism)
• Epithelial Cells (pathology)
• Epithelial-Mesenchymal Transition (genetics)
• Female
• Gene Expression Regulation, Neoplastic (genetics)
• Mammary Glands, Animal (pathology)
• Mammary Neoplasms, Animal (genetics, pathology)
• Mesenchymal Stem Cells (metabolism)
• Mice
• Mice, Knockout
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• Triple Negative Breast Neoplasms (genetics)