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 α (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.

[1]  D. Kufe,et al.  MUC1 oncoprotein activates the IkappaB kinase beta complex and constitutive NF-kappaB signalling. , 2007, Nature cell biology.

[2]  Vessela N Kristensen,et al.  Gene expression profiling of breast cancer in relation to estrogen receptor status and estrogen-metabolizing enzymes: clinical implications. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[3]  Xiaolong Wei,et al.  MUC1 oncoprotein stabilizes and activates estrogen receptor alpha. , 2006, Molecular cell.

[4]  Franck Molina,et al.  A Gene Expression Signature that Can Predict the Recurrence of Tamoxifen-Treated Primary Breast Cancer , 2008, Clinical Cancer Research.

[5]  Wei Wang,et al.  A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. , 2004, Cancer cell.

[6]  Gianluca Bontempi,et al.  Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen , 2008, BMC Genomics.

[7]  Bernard Roizman,et al.  STAT1 is overexpressed in tumors selected for radioresistance and confers protection from radiation in transduced sensitive cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[8]  D. Kufe,et al.  Nuclear Import of the MUC1-C Oncoprotein Is Mediated by Nucleoporin Nup62* , 2007, Journal of Biological Chemistry.

[9]  Bernard Roizman,et al.  Signal transducer and activator of transcription 1 regulates both cytotoxic and prosurvival functions in tumor cells. , 2007, Cancer research.

[10]  D. Kufe,et al.  The c-Src Tyrosine Kinase Regulates Signaling of the Human DF3/MUC1 Carcinoma-associated Antigen with GSK3β and β-Catenin* , 2001, The Journal of Biological Chemistry.

[11]  M. Loda,et al.  Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein. , 2003, Molecular cancer research : MCR.

[12]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[13]  M. Cronin,et al.  A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. , 2004, The New England journal of medicine.

[14]  B. Vincenzi,et al.  Hormono-biological therapy in metastatic breast cancer: preclinical evidence, clinical studies and future directions. , 2008, Expert Opinion on Biological Therapy.

[15]  J. Bergh,et al.  Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  V. Jordan,et al.  The estrogen receptor: a model for molecular medicine. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[17]  Margaret Gardiner-Garden,et al.  Identification of Functional Networks of Estrogen- and c-Myc-Responsive Genes and Their Relationship to Response to Tamoxifen Therapy in Breast Cancer , 2008, PloS one.

[18]  Xiaolong Wei,et al.  MUC1 Oncoprotein Stabilizes and Activates Estrogen Receptor α , 2006 .

[19]  H. L. Vos,et al.  A STAT-responsive Element in the Promoter of the Episialin/MUC1 Gene Is Involved in Its Overexpression in Carcinoma Cells* , 2001, The Journal of Biological Chemistry.

[20]  J. Schlom,et al.  Differential reactivity of a novel monoclonal antibody (DF3) with human malignant versus benign breast tumors. , 1984, Hybridoma.

[21]  P. Sismondi,et al.  Molecular identification of ERα‐positive breast cancer cells by the expression profile of an intrinsic set of estrogen regulated genes , 2004, Journal of cellular physiology.

[22]  Trevor Hastie,et al.  Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers , 2006, PLoS medicine.

[23]  Masha Kocherginsky,et al.  Progression of Barrett's metaplasia to adenocarcinoma is associated with the suppression of the transcriptional programs of epidermal differentiation. , 2005, Cancer research.

[24]  G. Glinsky,et al.  Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. , 2005, The Journal of clinical investigation.

[25]  Ash A. Alizadeh,et al.  Gene Expression Signature of Fibroblast Serum Response Predicts Human Cancer Progression: Similarities between Tumors and Wounds , 2004, PLoS biology.

[26]  F. Couch,et al.  A Two-Gene Expression Ratio of Homeobox 13 and Interleukin-17B Receptor for Prediction of Recurrence and Survival in Women Receiving Adjuvant Tamoxifen , 2006, Clinical Cancer Research.

[27]  Xiaolong Wei,et al.  Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response. , 2005, Cancer cell.

[28]  Joseph L Goldstein,et al.  SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. , 2002, The Journal of clinical investigation.

[29]  N. Peat,et al.  Analysis of the tissue-specific promoter of the MUC1 gene. , 1993, The Journal of biological chemistry.

[30]  D. Kufe,et al.  Characterization of cis-acting elements regulating transcription of the human DF3 breast carcinoma-associated antigen (MUC1) gene. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[31]  J. Menéndez,et al.  Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis , 2007, Nature Reviews Cancer.

[32]  Hemant Ishwaran,et al.  An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer , 2008, Proceedings of the National Academy of Sciences.

[33]  V. Jordan,et al.  Chemoprevention of breast cancer with selective oestrogen-receptor modulators , 2007, Nature Reviews Cancer.

[34]  L. Yin,et al.  MUC1 Oncoprotein Blocks Glycogen Synthase Kinase 3β–Mediated Phosphorylation and Degradation of β-Catenin , 2005 .

[35]  D. Kufe,et al.  Transcriptional regulation of DF3 gene expression in human MCF‐7 breast carcinoma cells , 1990, Journal of cellular physiology.

[36]  Samuel Hellman,et al.  Receiver operating characteristic analysis: a general tool for DNA array data filtration and performance estimation. , 2003, Genomics.

[37]  J. Swinnen,et al.  Androgen activation of the sterol regulatory element-binding protein pathway: Current insights. , 2006, Molecular endocrinology.

[38]  L. Yin,et al.  MUC1 oncoprotein blocks glycogen synthase kinase 3beta-mediated phosphorylation and degradation of beta-catenin. , 2005, Cancer research.

[39]  R. Lathe,et al.  A transcribed gene, containing a variable number of tandem repeats, codes for a human epithelial tumor antigen. cDNA cloning, expression of the transfected gene and over-expression in breast cancer tissue. , 1990, European journal of biochemistry.

[40]  D. Kufe,et al.  MUC1 oncoprotein activates the IκB kinase β complex and constitutive NF-κB signalling , 2007, Nature Cell Biology.

[41]  A. Nobel,et al.  Concordance among Gene-Expression – Based Predictors for Breast Cancer , 2011 .

[42]  Manuela Gariboldi,et al.  Limits of predictive models using microarray data for breast cancer clinical treatment outcome. , 2005, Journal of the National Cancer Institute.

[43]  Howard Y. Chang,et al.  Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[44]  R. Weichselbaum,et al.  Interaction of amifostine and ionizing radiation on transcriptional patterns of apoptotic genes expressed in human microvascular endothelial cells (HMEC). , 2004, International journal of radiation oncology, biology, physics.