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.

Neuropilin-1 is over-expressed in claudin-low breast cancer and promotes tumor progression through acquisition of stem cell characteristics and RAS/MAPK pathway activation

“…Evidence is accumulating that aberrant activation of the RAS/MAPK pathway is a key mechanism capable of driving transition to a claudin-low phenotype [ 11 , 47 ]. Despite demonstrably high RAS pathway signaling in a substantial proportion of breast tumors, RAS mutations occur relatively infrequently in human breast cancers, suggesting that engagement of the RAS pathway may be driven by alternate cooperative mechanisms [ 48 ].…”

Context-Dependent Roles of Claudins in Tumorigenesis

“…Claudin-low cancer represents a rare and biologically aggressive variant of epithelial tumor A claudin-low molecular subtype of breast cancer has been described as having low expression of claudin-3, -4, and -7 and E-cadherin, with concomitant stem cell features ( 65 ). It had been previously proposed that this breast cancer type originates from undifferentiated stem cells, which was challenged by a recent study indicating that the claudin-low subtype can arise from differentiated epithelial cells that assume a developmental trajectory where they progressively gain stem cell-like characteristics ( 66 ). In spite of the debating of its cell of origin, this subtype of high-grade invasive ductal breast carcinoma was found to lack luminal differentiation markers, and its cells most closely resemble mammary epithelial stem cells ( 65 ).…”

“…As claudins play roles in maintaining these functions and enhancing the CSC phenotype, the involvement of claudins in EMT is not surprising. The claudin-low molecular subtype of breast cancer has concomitant EMT and stem cell features ( 65 , 66 ). The expression of claudins is regulated by many signaling pathways and transcription factors (TFs), such as Wnt/β-catenin, Slug, and Snail, which are all involved in the EMT program ( Supplementary Table S1 ).…”

Models of pancreatic ductal adenocarcinoma

“…This may explain why several of the human pancreatic cancer cell lines that are commonly used in research carry two mutant KRAS alleles (e.g., AsPC-1, MIA PaCa-2, Capan-1, KP-3; source NCI RAS Initiative). The allelic imbalance is not unique to pancreatic cancer and was also observed in a triple-negative breast cancer (TNBC) model that develops claudin-low (i.e., mesenchymal-like) mammary tumors in response to a mammary epithelial-specific activation of KRAS G12D under the control of the endogenous KRAS locus [ 28 ]. Notably, the most commonly used human TNBC cell line to study metastatic breast cancer, MBA-MDA-231, carries mutations in KRAS , BRAF , and NF1 , underscoring the universality of an increase in RAS signaling strength during the progression of diverse cancer types.…”