Unknown,Transcriptomics,Genomics,Proteomics

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A Myc transcriptional program that is independent of EMT drives a poor prognosis tumor-propagating phenotype in HER2+ breast cancer

ABSTRACT: The HER2 (ERBB2) and MYC genes are commonly amplified genes in breast cancer, yet little is known about their molecular and clinical interaction. Using a novel chimeric mammary transgenic approach and in vitro models, we demonstrate markedly increased self renewal and tumour propagating capability of cells transformed with Her2 and c-Myc. Co-expression of both oncogenes in cultured cells led to a pronounced activation of a c-Myc transcriptional signature and acquisition of a self renewing phenotype independent of an EMT programme or regulation of cancer stem cell markers. We show that HER2 and c-MYC are frequently co-amplified in a clinical breast cancer cohort and that co-amplification is strongly associated with aggressive clinical behaviour and poor outcome. Lastly, we show that in patients receiving adjuvant chemotherapy (but not targeted anti-HER2 therapy), MYC amplification is associated with a poor outcome in HER2+ breast cancer patients. These findings demonstrate the importance of molecular context in oncogenic transformation and acquisition of a malignant stem-like phenotype and have important diagnostic and therapeutic consequences for the clinical management of HER2+ breast cancer. Gene expression analysis of Her2, Myc, and Her2 + Myc over expression on MCF10A cells, with MCF10A vector control comparison

ORGANISM(S): Homo sapiens

SUBMITTER: Daniel Roden

PROVIDER: E-GEOD-43730 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

c-Myc and Her2 cooperate to drive a stem-like phenotype with poor prognosis in breast cancer.

Nair R R Roden D L DL Teo W S WS McFarland A A Junankar S S Ye S S Nguyen A A Yang J J Nikolic I I Hui M M Morey A A Shah J J Pfefferle A D AD Usary J J Selinger C C Baker L A LA Armstrong N N Cowley M J MJ Naylor M J MJ Ormandy C J CJ Lakhani S R SR Herschkowitz J I JI Perou C M CM Kaplan W W O'Toole S A SA Swarbrick A A

Oncogene 20130923 30

The HER2 (ERBB2) and MYC genes are commonly amplified in breast cancer, yet little is known about their molecular and clinical interaction. Using a novel chimeric mammary transgenic approach and in vitro models, we demonstrate markedly increased self-renewal and tumour-propagating capability of cells transformed with Her2 and c-Myc. Coexpression of both oncoproteins in cultured cells led to the activation of a c-Myc transcriptional signature and acquisition of a self-renewing phenotype independe ...[more]

PMID: 24056965

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Project description:Visceral fat (VF) and subcutaneous fat (SF) are developmentally different tissues with different gene expression. Islet-1 (ISL1), a LIM-homeobox transcription factor with important developmental and regulatory function in islet, neural, and cardiac tissue, is virtually absent in SF but substantially expressed in the stromovascular [preadipocyte containing] fraction of VF; expression correlates negatively with adiposity in rodents and man. ISL1 expression is transiently increased in 3T3-L1 preadipocytes during early differentiation, suggesting a functional role. To examine the role of ISL1 in adipogenesis, we tested whether retroviral overexpression of ISL1 in 3T3-L1 preadipocytes affected their ability to differentiate into mature adipocytes. Terminal differentiation was assessed by Oil Red O [lipid droplet] staining and by immunoblot detection of adipocyte marker proteins, including aP2 and GLUT4. ISL1 significantly inhibited lipid droplet formation, reduced lipid accumulation (about 80% inhibition, p<0.05), and substantially inhibited aP2 and GLUT4 expression. ISL1 did not inhibit expression of C/EBPb and C/EBPd after induction of differentiation, but reduced PPARg and C/EBPa by >50% at both mRNA and protein level. In addition, the PPARg agonist, rosiglitazone, substantially rescued ISL1 inhibited adipogenesis in the absence of exogenous PPARg, and fully rescued in the presence of exogenous PPARg. In summary, ISL1 overexpression inhibited fat droplet formation, lipid accumulation, and adipocyte-specific gene expression; there was accompanying inhibition of C/EBPa, PPARg and downstream gene expression. We conclude that ISL1 overexpression inhibited adipocyte differentiation by inhibition of PPARg regulated gene expression. As abdominal obesity strongly correlates with insulin resistance, and cardiovascular risk, ISL1 up-regulation may impact abdominal obesity and its concomitant metabolic derangements. Total cellular RNA was isolated from 3T3-L1 cells expressing Flag-ISL1 or not at 48 h following treatment with differentiation cocktail. Individual RNA from biological triplicates was used for microarray analysis.

Dataset Information

A Myc transcriptional program that is independent of EMT drives a poor prognosis tumor-propagating phenotype in HER2+ breast cancer

Publications

c-Myc and Her2 cooperate to drive a stem-like phenotype with poor prognosis in breast cancer.

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