MUC1-induced alterations in a lipid metabolic gene network predict response of human breast cancers to tamoxifen treatment.
The mucin 1 (MUC1) oncoprotein is aberrantly overexpressed in human breast cancers. Although MUC1 modulates the activity of estrogen receptor alpha (ER), there is no information regarding the effects of MUC1 on global gene expression patterns and the potential role of MUC1-induced genes in predicting outcome for breast cancer patients. We have developed an experimental model of MUC1-induced transformation that has identified the activation of genes involved in cholesterol and fatty acid metabolism. A 38-gene set of experimentally derived MUC1-induced genes associated with lipid metabolism was applied to the analysis of ER(+) breast cancer patients treated with tamoxifen. The results obtained from 2 independent databases demonstrate that patients overexpressing MUC1 and the lipid metabolic pathways are at significantly higher risk for death and recurrence/distant metastasis. By contrast, these genes were not predictive in untreated patients. Furthermore, a positive correlation was found between expression of the 38-gene set and the ER signaling pathway. These findings indicate that (i) MUC1 regulates cholesterol and fatty acid metabolism, and (ii) activation of these pathways in ER(+) breast cancers predicts failure to tamoxifen treatment.
Pitroda
Sean P
SP
Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.
Khodarev
Nikolai N
NN
Beckett
Michael A
MA
Kufe
Donald W
DW
Weichselbaum
Ralph R
RR
D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy*; D002784:Cholesterol / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha; D005260:Female; D053263:Gene Regulatory Networks; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D018396:Mucin-1 / Q000502:physiology*; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins; D011237:Predictive Value of Tests; D011379:Prognosis; D012008:Recurrence; D015996:Survival Rate; D015533:Transcriptional Activation
D047628:Estrogen Receptor alpha; D018396:Mucin-1; D009363:Neoplasm Proteins; D002784:Cholesterol