Comprehensive characterization of claudin-low breast tumors reflects the impact of the cell-of-origin on cancer evolution

Roxane M Pommier,Frédéric Hollande,Agnès Tissier,Maria Ouzounova,Emilie Thomas,Alain Puisieux,Anne-Pierre Morel,Laurie Tonon,Janice Kielbassa,Anne-Sophie Sertier,Anthony Ferrari,Pierre Martinez,Amélien Sanlaville

doi:10.1038/s41467-020-17249-7

Abstract

Claudin-low breast cancers are aggressive tumors defined by the low expression of key components of cellular junctions, associated with mesenchymal and stemness features. Although they are generally considered as the most primitive breast malignancies, their histogenesis remains elusive. Here we show that this molecular subtype of breast cancers exhibits a significant diversity, comprising three main subgroups that emerge from unique evolutionary processes. Genetic, gene methylation and gene expression analyses reveal that two of the subgroups relate, respectively, to luminal breast cancers and basal-like breast cancers through the activation of an EMT process over the course of tumor progression. The third subgroup is closely related to normal human mammary stem cells. This unique subgroup of breast cancers shows a paucity of genomic aberrations and a low frequency of TP53 mutations, supporting the emerging notion that the intrinsic properties of the cell-of-origin constitute a major determinant of the genetic history of tumorigenesis.

Highlights

Claudin-low breast cancers are aggressive tumors defined by the low expression of key components of cellular junctions, associated with mesenchymal and stemness features
Supporting the prevailing hypothesis that some of these tumors are generated from basal-like breast cancers, the comprehensive characterization of METABRIC and The Cancer Genome Atlas Network (TCGA) databases have revealed the existence of claudin-low breast cancers (CL3 subgroup) with characteristics of basal mammary epithelial cells and of basal-like breast cancers
These traits include the hypomethylation of genes related to basal-related pathways, the hypermethylation of genes related to luminal-related pathways, a high level of expression of proliferation-related genes and a strongly disturbed genomic landscape

Summary

Introduction

Claudin-low breast cancers are aggressive tumors defined by the low expression of key components of cellular junctions, associated with mesenchymal and stemness features. Providing early insights into this diversity, gene-expression profiling analyses initially resulted in the identification of four clinically relevant molecular subtypes, known as intrinsic subtypes (luminal A, luminal B, HER2-enriched and basal-like, according to the PAM50 classification) mostly corresponding to hormone receptor and HER2 status, and a normal breast-like group[1,2,3,4] Among these intrinsic subtypes, the basal-like subtype appears to be the most distinct, as it is characterized by the unique expression of cytokeratins typically expressed by the basal layer of the skin and a very low level of expression of luminal-related genes[2,5]. To comprehensively characterize the claudin-low breast tumor subtype, we used a multi-omics approach that reveal the existence of three distinct subgroups with specific transcriptomic, epigenetic, and genetic characteristics, strongly supporting the hypothesis of different cells-of-origin

Methods

Results

Conclusion