Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression data from retroviral vector-infected immortalized mouse embryonic fibroblasts (MEFs)

ABSTRACT: Cultured cancer cells exhibit substantial phenotypic heterogeneity when measured in a variety of ways such as sensitivity to drugs or the capacity to grow under various conditions. Among these, the ability to exhibit anchorage-independent cell growth (colony forming capacity in semisolid media) has been considered to be fundamental in cancer biology because it has been connected with tumor cell aggressiveness in vivo such as tumorigenic and metastatic potentials, and also utilized as a marker for in vitro transformation. Although multiple genetic factors for anchorage-independence have been identified, the molecular basis for this capacity is still largely unknown. To investigate the molecular mechanisms underlying anchorage-independent cell growth, we have used genome-wide DNA microarray studies to develop an expression signature associated with this phenotype. Using this signature, we identify a program of activated mitochondrial biogenesis associated with the phenotype of anchorage-independent growth and importantly, we demonstrate that this phenotype predicts potential for metastasis in primary breast and lung tumors. Keywords: c-Myc or v-Src retroviral vector-infected immortalized mouse embryonic fibroblasts. Expression data of c-Myc and v-Src transformed MEFs was used to validate an expression signature generated from human cultured breast cancer cell lines with anchorage-independent growth ability.

ORGANISM(S): Mus musculus

SUBMITTER: Seiichi Mori

PROVIDER: E-GEOD-15161 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Anchorage-independent cell growth signature identifies tumors with metastatic potential.

Mori S S Chang J T JT Andrechek E R ER Matsumura N N Baba T T Yao G G Kim J W JW Gatza M M Murphy S S Nevins J R JR

Oncogene 20090601 31

The oncogenic phenotype is complex, resulting from the accumulation of multiple somatic mutations that lead to the deregulation of growth regulatory and cell fate controlling activities and pathways. The ability to dissect this complexity, so as to reveal discrete aspects of the biology underlying the oncogenic phenotype, is critical to understanding the various mechanisms of disease as well as to reveal opportunities for novel therapeutic strategies. Previous work has characterized the process ...[more]

PMID: 19483725

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Project description:Cultured cancer cells exhibit substantial phenotypic heterogeneity when measured in a variety of ways such as sensitivity to drugs or the capacity to grow under various conditions. Among these, the ability to exhibit anchorage-independent cell growth (colony forming capacity in semisolid media), has been considered to be fundamental in cancer biology, because it has been connected with tumor cell aggressiveness in vivo such as tumorigenic and metastatic potentials, and also utilized as a marker for in vitro transformation. Although multiple genetic factors for anchorage-independence have been identified, the molecular basis for this capacity is still largely unknown. To investigate the molecular mechanisms underlying anchorage independent cell growth, we have used genome-wide DNA microarray studies to develop an expression signature associated with this phenotype. Using this signature, we identify a program of activated mitochondrial biogenesis associated with the phenotype of anchorage-independent growth and importantly, we demonstrate that this phenotype predicts potential for metastasis in primary breast and lung tumors. Keywords: Breast cancer cell lines with various colony-forming ability To develop an expression signature reflecting the capacity for anchorage-independent cell growth, we first carried out colony formation assays with 19 breast cancer cell lines in suspension culture dish with methyl-cellulose containing media. Starting with 20,000 plated cells, five cell lines (MDA-MB-361, HCC38, ZR75, Hs578T and BT483) gave rise to less than 20 colonies, while 8 cell lines (MCF7, MDA-MB-231, BT20, SKBR3, MDA-MB-435s, T47D and BT474) showed formation of more than 500 colonies. The rest of the cell lines showed an intermediate phenotype in colony forming ability (20-200 colonies; HCC1143, HCC1806, HCC1428, MDA-MB-453, CAMA1, BT549 and MDA-MB-157). Among 19 cell lines, 11 cell lines have duplicates of expression data in a different batch. We removed the batch effect of this Affymetrix expression data using ComBat according to the instruction of http://statistics.byu.edu/johnson/ComBat/Abstract.html. Therefore, this dataset is a combined and standardized data that are originally RMA formatted.

Project description:Approximately 30% of metastatic breast cancers harbor estrogen receptor α (ERα/ESR1) mutations that are associated with resistance to endocrine therapy and shorter patient survival. How these ERα mutations elicit an aggressive tumor phenotype was largely unknown. Recently, we reported cell lines in which the wild-type ESR1 gene is replaced by the two most common ERα mutations, ERαY537S and ERαD538G. Here we use transcriptome analysis to demonstrate that ERαY537S cells exhibit a unique expression profile and phenotype, and identify an important role for Myc in the increased growth rate, ligand independent cell proliferation, and partial resistance to tamoxifen and fulvestrant of cells expressing the ERαY537S and ERαD538G mutations. Notably, the T47DERαY537S (TYS) cells exhibit a markedly different phenotype and transcriptome than the parental T47D cells and T47DERαD538G (TDG) cells. Consistent with their estrogen-independent proliferation, RNAseq shows the TYS and TDG cells exhibit estrogen independent gene expression patterns. Gene set enrichment analysis showed Myc target pathways are highly induced in both mutant cell lines. Unlike the parental T47D cells, in TYS and TDG cells Myc mRNA and protein exhibit constitutive, fulevestrant-resistant expression. Moreover, chromatin immunoprecipitation (ChIP) showed that ERαY537S and ERαD538G exhibit constitutive, fulvestrant-resistant, recruitment to the Myc enhancer region. Myc knockdown showed that Myc protein is required for ligand independent proliferation of TYS and TDG cells. Constitutive MYC expression in T47D cells, to levels similar to those in TYS and TDG cells, partially recapitulated the aggressive phenotypes of the TYS and TDG cells. Our study demonstrates a previously undescribed role for constitutive and antiestrogen resistant Myc expression in the aggressive phenotype exhibited by breast cancer cells expressing ERα mutations and provides powerful tools for identifying pathways that contribute to the ERα mutant phenotype.

Dataset Information

Expression data from retroviral vector-infected immortalized mouse embryonic fibroblasts (MEFs)

Publications

Anchorage-independent cell growth signature identifies tumors with metastatic potential.

Similar Datasets

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