Figure 2

Schematic illustrations of the five major clusters that represent the molecular subtypes of breast cancer. Perou and colleagues [11] carried out a cDNA microarray analysis of 38 invasive breast cancers, 1 ductal carcinoma in situ, 1 fibroadenoma and 3 normal breast samples, and a number of biological replicates of tumors from the same patients and defined an 'intrinsic gene' list (that is, genes that vary more between tumors from different patients compared with samples from the same tumor/patient). Hierarchical clustering analysis using these 'intrinsic' genes led to the identification of four subtypes: luminal, normal breast-like, human epidermal growth factor receptor 2 (HER2), and basal-like. In subsequent studies, it was demonstrated that similar molecular subtypes of breast cancer could be identified in multiple cohorts and that luminal cancers could be subclassified into two groups (luminal A and B) [12] or three groups (luminal A, B, and C) [13]. The estrogen receptor (ER)-positive branch of the dendrogram contains the luminal tumors, which express low-molecular weight cytokeratins 8/18, ER, and genes associated with an active ER pathway [2, 3, 11–13, 17, 26, 34]. Luminal A tumors (dark blue) present high levels of expression of ER-activated genes and low proliferation rates and are associated with an excellent prognosis, whereas luminal B breast cancers (light blue) are more often of higher histological grade and have higher proliferation rates and a worse prognosis [2, 3, 11–13, 17, 26, 34]. The ER-negative branch includes at least three subtypes: normal breast-like, HER2, and basal-like. HER2 tumors (purple) overexpress HER2 and genes associated with the HER2 amplicon on 17q12 (that is, GRB7) and/or the HER2 pathway [2, 3, 11–13, 17, 26, 34]. Basal-like tumors (red) express genes usually found in normal basal/myoepithelial cells of the breast, including high-molecular weight cytokeratins (5 and 17), caveolins 1 and 2, P-cadherin, nestin, CD44, and EGFR [20]. Morphological and immunohistochemical features of basal-like cancers are similar to those described for tumors arising in BRCA1 germ-line mutation carriers [20]. The HER2 and basal-like subgroups share an aggressive clinical behavior. Normal breast-like cancers (green) are still poorly characterized [3, 22] and there is evidence to suggest that they may constitute an artefact of gene expression profiling associated with a disproportionately high content of normal breast tissue [3, 17, 26, 34].