The effect of ACSL4 expression on overall gene expression in breast cancer cell lines
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE40968 | GEO | 2012/09/19
SECONDARY ACCESSION(S): PRJNA175454
REPOSITORIES: GEO
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Project description:ACSL4 expression appears to be inversely associated with steroid hormone and growth factor receptor expression in breast cancer and positively correlated with an aggressive breast cancer phenotype. Neither MCF-7 nor SKBr3 cells normally express ACSL4, and when manipulated to do so, develop basal-like characteristics, including increased proliferation, migration and anchorage independent growth. We used an Affymetrix array platform to assess changes in individual gene expression as a function of conditional and stable expression of ACSL4 in MCF-7 and SKBr3 cells. In experiment 1, MCF-7 Tet-ON cells were transfected with ACSL4 cDNA and induced to express ACSL4 by addition of 1ug/ml of doxycycline (A) or vehicle (C) for 72 hours. Three controls (C) and three doxycycline-induced (A) samples were evaluated for gene expression. In experiment 2, MCF-7 cells were stably transfected with either an empty vector (C) or Lenti-ORF-ACSL4 (A). In experiment 3, SKBr3 cells were stably transfected with either an empty vector (C) or Lenti-ORF-ACSL4 (A).
2012-09-19 | E-GEOD-40968 | biostudies-arrayexpress
Project description:Triple-Negative Breast Cancer (TNBC) has profound unmet medical need globally for its devastating clinical outcome associated with rapid metastasis and lack of targeted therapies. Recently, lipid metabolic reprogramming especially fatty acid oxidation (FAO) has emerged as a major driver of breast cancer metastasis. Analyzing the expression of major FAO regulatory genes in breast cancer, we found selective overexpression of acyl-CoA synthetase 4 (ACSL4) in TNBC, which is primarily attributed by the absence of progesterone receptor (PR). Loss of ACSL4 function, by genetic ablation or pharmacological inhibition significantly reduces metastatic potential of TNBC. Global transcriptome analysis reveals that ACSL4 activity positively influences the gene expression related to TNBC migration and invasion. Mechanistically, ACSL4 modulates FAO and intracellular acetyl-CoA levels, leading to hyper-acetylation of particularly H3K9ac and H3K27ac marks resulting in overexpression of SNAIL during the course of TNBC metastatic spread to lymph node and lung. Further, human TNBC metastasis exhibits positive correlation among ACSL4, H3K9ac, H3K27ac, and SNAIL expression. Altogether, our findings provide new molecular insights regarding the intricate interplay between metabolic alterations and epigenetic modifications, intertwined to orchestrate TNBC metastasis and posit a rational understanding for the development of ACSL4 inhibitors as a targeted therapy against TNBC.
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Project description:Using microarray analysis, we identified a unique ras superfamily gene, termed RERG (ras-related and estrogen-regulated growth inhibitor), whose expression was decreased or lost in a significant percentage of primary human breast tumors that show a poor clinical prognosis. Importantly, high RERG expression correlated with expression of a set of genes that define a breast tumor subtype that is estrogen receptor-positive and associated with a slow rate of tumor cell proliferation and a favorable prognosis for these cancer patients. RERG mRNA expression was induced rapidly in MCF-7 cells stimulated by beta-estradiol and repressed by tamoxifen treatment. Like Ras, RERG protein exhibited intrinsic GDP/GTP binding and GTP hydrolysis activity. Unlike Ras proteins, RERG lacks a known recognition signal for COOH-terminal prenylation and was localized primarily in the cytoplasm. Expression of RERG protein in MCF-7 breast carcinoma cells resulted in a significant inhibition of both anchorage-dependent and anchorage-independent growth in vitro and inhibited tumor formation in nude mice. These features of RERG are strikingly different from most Ras superfamily GTP-binding pro-teins and suggest that the loss of RERG expression may contribute to breast tumorigenesis.
2005-06-22 | E-SMDB-1443 | biostudies-arrayexpress
Project description:Using microarray analysis, we identified a unique ras superfamily gene, termed RERG (ras-related and estrogen-regulated growth inhibitor), whose expression was decreased or lost in a significant percentage of primary human breast tumors that show a poor clinical prognosis. Importantly, high RERG expression correlated with expression of a set of genes that define a breast tumor subtype that is estrogen receptor-positive and associated with a slow rate of tumor cell proliferation and a favorable prognosis for these cancer patients. RERG mRNA expression was induced rapidly in MCF-7 cells stimulated by beta-estradiol and repressed by tamoxifen treatment. Like Ras, RERG protein exhibited intrinsic GDP/GTP binding and GTP hydrolysis activity. Unlike Ras proteins, RERG lacks a known recognition signal for COOH-terminal prenylation and was localized primarily in the cytoplasm. Expression of RERG protein in MCF-7 breast carcinoma cells resulted in a significant inhibition of both anchorage-dependent and anchorage-independent growth in vitro and inhibited tumor formation in nude mice. These features of RERG are strikingly different from most Ras superfamily GTP-binding pro-teins and suggest that the loss of RERG expression may contribute to breast tumorigenesis. Groups of assays that are related as part of a time series. Computed
2005-07-23 | E-GEOD-2987 | biostudies-arrayexpress
Project description:Using microarray analysis, we identified a unique ras superfamily gene, termed RERG (ras-related and estrogen-regulated growth inhibitor), whose expression was decreased or lost in a significant percentage of primary human breast tumors that show a poor clinical prognosis. Importantly, high RERG expression correlated with expression of a set of genes that define a breast tumor subtype that is estrogen receptor-positive and associated with a slow rate of tumor cell proliferation and a favorable prognosis for these cancer patients. RERG mRNA expression was induced rapidly in MCF-7 cells stimulated by beta-estradiol and repressed by tamoxifen treatment. Like Ras, RERG protein exhibited intrinsic GDP/GTP binding and GTP hydrolysis activity. Unlike Ras proteins, RERG lacks a known recognition signal for COOH-terminal prenylation and was localized primarily in the cytoplasm. Expression of RERG protein in MCF-7 breast carcinoma cells resulted in a significant inhibition of both anchorage-dependent and anchorage-independent growth in vitro and inhibited tumor formation in nude mice. These features of RERG are strikingly different from most Ras superfamily GTP-binding pro-teins and suggest that the loss of RERG expression may contribute to breast tumorigenesis. Groups of assays that are related as part of a time series. Keywords: time_series_design
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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.
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