Use of a gene profile to identify molecular subtypes of breast cancer.

Abstract

537 Background: Classification of breast cancer into molecular subtypes may be important for the proper selection of therapy, as tumors with seemingly similar biology can have strikingly different clinical outcomes. We have previously developed an 80-gene molecular subtyping profile (BluePrint) for the classification of breast cancer into three molecular subtypes: triple-negative (“Basal-type”); hormone receptor-positive (“Luminal-type”) and ERBB2-positive (“ERBB2-type”). In this study, we sought to determine if Luminal-type tumors are characterized by active ER signaling. Methods: ERα ChIP-seq data from proliferating MCF-7 breast cancer cells was used from a publically available dataset [Ross-Innes, 2010]. The transcription start sites of the 58 genes in the gene set that identifies the Luminal-type subgroup were determined after which the presence of Estrogen Receptor binding sites was analyzed within a window of −/+ 20 kb from the transcription start site. The sequence track was visualized using the UCSC genome browser (http://genome.ucsc.edu/). Peak intensity was determined from the tag count. Results: We found that 32 of the 58 Luminal profile genes have ERα binding sites adjacent to their promoters (55%), whereas only 28% of all RefSeq genes (24,000) have ERα binding sites in their promoters. This result indicates that the genes associated with Luminal-type breast cancer are significantly enriched for those that have ERα binding sites adjacent to their promoters (p= 1.2e-5). Conclusions: The group of genes identifying Luminal-type breast cancer is highly enriched for genes having an Estrogen Receptor binding site in their promoter-proximal region suggesting that these genes are direct targets of the Estrogen Receptor. As such, the classification of breast tumors as “Luminal” by BluePrint most likely describes breast cancers that depend on Estrogen Receptor signaling. These data suggest that Luminal-type breast tumors are likely to respond to endocrine therapy.