Abstract
IntroductionIn breast cancer, gene expression analyses have defined five tumor subtypes (luminal A, luminal B, HER2-enriched, basal-like and claudin-low), each of which has unique biologic and prognostic features. Here, we comprehensively characterize the recently identified claudin-low tumor subtype.MethodsThe clinical, pathological and biological features of claudin-low tumors were compared to the other tumor subtypes using an updated human tumor database and multiple independent data sets. These main features of claudin-low tumors were also evaluated in a panel of breast cancer cell lines and genetically engineered mouse models.ResultsClaudin-low tumors are characterized by the low to absent expression of luminal differentiation markers, high enrichment for epithelial-to-mesenchymal transition markers, immune response genes and cancer stem cell-like features. Clinically, the majority of claudin-low tumors are poor prognosis estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and epidermal growth factor receptor 2 (HER2)-negative (triple negative) invasive ductal carcinomas with a high frequency of metaplastic and medullary differentiation. They also have a response rate to standard preoperative chemotherapy that is intermediate between that of basal-like and luminal tumors. Interestingly, we show that a group of highly utilized breast cancer cell lines, and several genetically engineered mouse models, express the claudin-low phenotype. Finally, we confirm that a prognostically relevant differentiation hierarchy exists across all breast cancers in which the claudin-low subtype most closely resembles the mammary epithelial stem cell.ConclusionsThese results should help to improve our understanding of the biologic heterogeneity of breast cancer and provide tools for the further evaluation of the unique biology of claudin-low tumors and cell lines.
Highlights
In breast cancer, gene expression analyses have defined five tumor subtypes, each of which has unique biologic and prognostic features
Molecular characterization of the claudin-low breast tumor subtype To identify the molecular characteristics of claudin-low tumors, we created a large genomic data set by combining three of our previously published data sets [5,6,9] and included 37 new tumor samples (n = 337; UNC337, Gene Expression Omnibus (GEO) series GSE18229)
The validity of the claudin-low sample cluster was confirmed by parsing the dendogram with SigClust [22] (P < 0.001); notably, this clustering analysis placed the claudin-low tumors in close proximity to the basal-like subtype and was composed of 32 arrays, representing 32 patients (~12% of all patients)
Summary
Gene expression analyses have defined five tumor subtypes (luminal A, luminal B, HER2-enriched, basal-like and claudin-low), each of which has unique biologic and prognostic features. In 2007, we identified a new molecular subtype, referred to as claudin-low, using 13 samples [5] These distinct tumors were found in both human and murine breast tumor data. We comprehensively characterize the claudin-low subtype using an updated human tumor database and multiple independent data sets and present the pathological and chemotherapy response characteristics of this subtype of “triple negative” breast cancers. In contrast to the basal-like subtype, we provide evidence that claudin-low tumors are more enriched in epithelialto-mesenchymal transition (EMT) features, immune system responses, and stem cell-associated biological processes. The molecular characterization of the claudin-low intrinsic subtype in tumors and cell lines reveals a breast cancer differentiation hierarchy that resembles the normal epithelial mammary developmental cascade
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