Abstract
The claudin-low breast cancer subtype is defined by gene expression characteristics and encompasses a remarkably diverse range of breast tumors. Here, we investigate genomic, transcriptomic, and clinical features of claudin-low breast tumors. We show that claudin-low is not simply a subtype analogous to the intrinsic subtypes (basal-like, HER2-enriched, luminal A, luminal B and normal-like) as previously portrayed, but is a complex additional phenotype which may permeate breast tumors of various intrinsic subtypes. Claudin-low tumors are distinguished by low genomic instability, mutational burden and proliferation levels, and high levels of immune and stromal cell infiltration. In other aspects, claudin-low tumors reflect characteristics of their intrinsic subtype. Finally, we explore an alternative method for identifying claudin-low tumors and thereby uncover potential weaknesses in the established claudin-low classifier. In sum, these findings elucidate the heterogeneity in claudin-low breast tumors, and substantiate a re-definition of claudin-low as a cancer phenotype.
Highlights
The claudin-low breast cancer subtype is defined by gene expression characteristics and encompasses a remarkably diverse range of breast tumors
We explore an alternative method for identifying claudin-low tumors, and demonstrate that the nine-cell line claudin-low predictor[12] may be overly inclusive in classifying tumors with marked immune and stromal infiltration as claudin-low
These findings indicate that the expression of estrogen receptor (ER) in claudin-low tumors is reflected in their intrinsic subtype, and that characterizing claudin-low tumors as a triple negative subgroup of breast cancer[9,12] is an oversimplification
Summary
The claudin-low breast cancer subtype is defined by gene expression characteristics and encompasses a remarkably diverse range of breast tumors. The claudin-low breast cancer subtype was discovered 7 years later in an integrated analysis of human and murine mammary tumors[3]. The claudin-low breast cancer subtype is defined by gene expression characteristics, most prominently: Low expression of cell–cell adhesion genes, high expression of epithelial–mesenchymal transition (EMT) genes, and stem cell-like/less differentiated gene expression patterns[12]. Beyond these gene expression features, claudin-low tumors have marked immune and stromal cell infiltration[9,12], but are in many other aspects remarkably heterogeneous. We explore an alternative method for identifying claudin-low tumors, and demonstrate that the nine-cell line claudin-low predictor[12] may be overly inclusive in classifying tumors with marked immune and stromal infiltration as claudin-low
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