Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer

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.

Claudin-2 is selectively enriched in and promotes the formation of breast cancer liver metastases through engagement of integrin complexes

“…Claudin-2 and breast cancer liver metastasis S Tabariès et al by features of an epithelial-to-mesenchymal transition, enhanced stem cell characteristics and resistance to chemotherapy (Creighton et al, 2009(Creighton et al, , 2010Hennessy et al, 2009;Prat et al, 2010;Taube et al, 2010). At the present time, the status of claudin-2 expression within these 'claudin-low' tumors has not been described.…”

Genomic predictors of response to doxorubicin versus docetaxel in primary breast cancer

“…Tumors were classified into molecular intrinsic subtypes based either on IHC/FISH parameters or using gene expression profiles [20][21][22] .The first method was based on an immunopanel of 4 biomarkers previously described by Hugh et al [22] The second approach was based on the "gold-standard" of gene expression profiles as assayed by DNA microarrays. The background subtracted Lowess normalized log2 ratio of Cy3 and Cy5 intensity values were retrieved and used for all subsequent analyses.…”

“…Tumors were classified into an intrinsic subtype (Luminal A, Luminal B, Her2-enriched, Basal-like and Normal-like) using the PAM50 50-gene assays a as described in Parker et al [19]. In addition, a recent identified subtype, namely Claudin-low, was also scored for using a centroid based predictor for this subtype [21]; in total, these two predictors (i.e. PAM50 and Claudin-low versus not, result in a 6 subtype classification system that is Luminal A, Luminal B, Basal-like, HER2-enriched, Claudin-low, and Normal-like).…”

Induction of a novel isoform of the lncRNA HOTAIR in Claudin‐low breast cancer cells attached to extracellular matrix

“…We set out to explore ECM‐mediated regulation of expression of the lncRNA HOTAIR in Claudin‐low breast cancer cells using lrECM 3D culture (Kenny et al ., 2007b; Prat et al ., 2010). We chose Claudin‐low MDA‐MB‐231 and Hs578T cells because of their invasive and metastatic competence (Neve et al ., 2006; Prat et al ., 2010).…”

“…Claudin‐low breast cancer cells are enriched with the genes that are critical to cellular responses to ECM (Charafe‐Jauffret et al ., 2009; Prat et al ., 2010). Therefore, understanding of cancer biology of Claudin‐low breast cancer cells attached to ECM is particularly important.…”