Highly metastatic claudin-low mammary cancers can originate from luminal epithelial 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 RNA of 6 mammary tumor cell lines was sequenced. 3 off_dox cell lines that were left untreated and their 3 isogenic cell lines that were treated with Doxycycline. The 3 cell lines represent biological replicates and are derived from distinct mammary tumors. Additionally, the RNA of 10 primary mammary tumors [from the MMTV-Flp FSF-Kras(G12D) p53(R172H)] was sequenced. The tumors all originate from distinct animals and were not treated. The tumors all represent biological replicates.