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

Patrick D Rädler,Aleata A Triplett,Robert D Cardiff,Barbara L Wehde,Hallgeir Rui,Jonathan H Shepherd,Kay-Uwe Wagner,Adam D Pfefferle,Hridaya Shrestha,Charles M Perou

doi:10.1038/s41467-021-23957-5

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.

Highlights

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
We can demonstrate that luminal epithelial cells can give rise to basal-like and claudin-low mammary cancers when exogenous or endogenous mutant RAS is expressed in an epithelial cell lineage-independent manner
All tumors were comprised of cancer cells that expressed cytokeratin 8 (CK8) and cytokeratin 14 (CK14), and a closer examination revealed that many cancer cells were dual positive for both cytokeratins (Fig. 1b, lower)

Summary

Introduction

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. A common characteristic of many TNBCs, including claudin-low tumors, are mutations in Trp[53] and members of the PI3K/AKT pathway[5] This breast cancer subtype exhibits a strong activation of RAS/MAP kinase signaling due to amplification of KRAS and BRAF, as well as loss of NF14,10,11. MDA-MB-231 cells carry mutations in BRAF13 and NF1 (COSMIC) in addition to oncogenic KRAS, suggesting that high levels of RAS/MAP kinase signaling might play critical roles in the cellular plasticity and metastatic characteristics This idea might be supported by recent bioinformatic studies that show that increased activation of the RAS pathway is a recurrent feature across all claudin-low breast cancers[14,15]. This study reveals that the degree of cellular plasticity of claudinlow cancer cells is being continuously upheld by RAS-dependent and RAS-independent molecular pathways

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Conclusion