Meta-analysis and gene set enrichment relative to ER status reveal elevated activity of MYC and E2F in the "basal" breast cancer subgroup.
Background: Breast cancers fall into two major classes depending on their estrogen receptor (ER) status. ER+ and ER- tumors have very different molecular phenotypes, and may have distinct cells of origin. ER- tumors generally fail to respond to endocrine therapy and have a poorer prognosis. To develop a comprehensive understanding of the gene networks and pathways active in ER+ compared to ER- breast cancers, we performed a meta-analysis of Grade 3 breast cancers from five published datasets. Results: A measure of association with ER status taking into account intra- and inter-study variability was calculated for every probe set. This meta-analysis revealed that ER-/Grade 3 tumors showed increased expression of proliferation-associated functional categories when compared to ER+/Grade 3 tumors. Using Gene Set Enrichment Analysis we show that transcript levels of direct transcriptional targets of ER are lower in ER- tumors, but that expression of other estrogen-induced genes is higher in ER- tumors. In the case of the estrogen-regulated MYC gene and the E2F family of genes, transcript levels of both direct targets and other targets are significantly higher in ER- tumors. The increased expression of targets of MYC and E2F is particularly pronounced in the ?basal? subgroup of ER- tumors. Conclusions: Over-expression or constitutive activation of MYC, possibly in conjunction with elevated E2F activity, may lead to the induction of a set of genes characteristic of the estrogen response thereby contributing to increased proliferation in ER- breast tumors, particularly in the basal subgroup.
|Authors||Alles, C.M.; Gardiner-Garden, M.; Nott, D.J.; Wang, Y.; Fuekens, J.A.; Sutherland, R.L.; Musgrove, E.A.; Ormandy, C.J.|
|Publisher Name||PLoS ONE|
|Published Date||2009-03-09 00:00:00|