Identification of cell-of-origin breast tumor subtypes in inflammatory breast cancer by gene expression profiling

Abstract

Inflammatory breast cancer (IBC) is an aggressive form of locally advanced breast cancer with high metastatic potential. Most patients have lymph node involvement at the time of diagnosis and 1/3 of the patients have distant metastases. In a previous study, we demonstrated that IBC is a distinct form of breast cancer in comparison with non-IBC. The aim of this study was to investigate the presence of the different molecular subtypes in our data set of 16 IBC and 18 non-IBC specimen. Therefore, we selected an 'intrinsic gene set' of 144 genes, present on our cDNA chips and common to the 'intrinsic gene set' described by Sorlie et al. [PNAS, 2003]. This set of genes was tested for performance in the Norway/Stanford data set by unsupervised hierarchical clustering. Expression centroids were then calculated for the core members of each of the five subclasses in the Norway/Stanford data set and used to classify our own specimens by calculating Spearman correlations between each sample and each centroid. We identified the same cell-of-origin subtypes in IBC as those already described in non-IBC. The classification was in good agreement with immunohistochemical data for estrogen receptor protein expression and cytokeratin 5/6 protein expression. Confirmation was done by an alternative unsupervised hierarchical clustering method. The robustness of this classification was assessed by an unsupervised hierarchical clustering with an alternative gene set of 141 genes related to the cell-of-origin subtypes, selected using a discriminating score and iterative random permutation testing. The contribution of the different cell-of-origin subtypes to the IBC phenotype was investigated by principal component analysis. Generally, the combined ErbB2-overexpressing and basal-like cluster was more expressed in IBC compared to non-IBC, whereas the combined luminal A, luminal B and normal-like cluster was more pronounced in non-IBC compared to IBC. The presence of the same molecular cell-of-origin subtypes in IBC as in non-IBC does not exclude the specific molecular nature of IBC, since gene lists that characterize IBC and non-IBC are entirely different from gene lists that define the different cell-of-origin subtypes, as evidenced by principal component analysis.

Distinct molecular phenotype of inflammatory breast cancer compared to non-inflammatory breast cancer using Affymetrix-based genome-wide gene-expression analysis

“…Using cDNA microarrays, Bertucci et al (2004) and Van Laere et al (2005) identified gene-expression signatures associated with the IBC phenotype. Using the same expression data sets, both studies demonstrated the presence of the same cell-of-origin breast cancer subtypes in IBC (Bertucci et al, 2005;Van Laere et al, 2006a), as was originally described for non-IBC (Perou et al, 2000). In depth analysis of genes differentially expressed between breast tumour samples from patients with IBC and other breast tumour samples revealed a potential hyperactivation of NF-kB in IBC (Van Laere et al, 2005), which was validated and confirmed in an independent study (Van Laere et al, 2006b).…”

“…The presence of different breast cancer cell-of-origin subtypes has been repeatedly observed in IBC (Bertucci et al, 2005;Van Laere et al, 2006a). We have shown that IBC primarily segregates into the basal-like or ErbB2-overexpressing subgroups (Van Laere et al, 2006a).…”

“…Detailed methodology is described in Van Laere et al (2006a). Briefly, the intrinsic gene list was mapped onto our informative gene list resulting in 347 informative and intrinsic genes.…”

“…We have shown that IBC primarily segregates into the basal-like or ErbB2-overexpressing subgroups (Van Laere et al, 2006a). We have investigated the presence of the different cell-oforigin subtypes in the current data set using a centroid-mediated clustering algorithm.…”

MicroRNA expression profiling identifies decreased expression of miR-205 in inflammatory breast cancer

“…The few published mRNA expression profiling studies to date have indicated that transcriptional heterogeneity exists in inflammatory breast cancer as extensively as in noninflammatory breast cancer, and that the established molecular subtypes such as luminal, HER2-positive, and basal-type can be identified in inflammatory breast cancer. [5][6][7][8][9][10][11][12][13][14][15][16] Although some of the studies have demonstrated differences in mRNA expression levels between inflammatory breast cancer and noninflammatory breast cancer samples, a specific inflammatory breast cancer signature cannot be deduced from these studies.…”