Unknown,Transcriptomics,Genomics,Proteomics

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A Transcriptional Signature and Common Gene Networks Link Cancer with Metabolic Syndrome and Auto-immune Diseases

ABSTRACT: Epidemiological studies have revealed concurrence of specific cancers with other disease states such as metabolic syndrome, inflammatory disease and autoimmune disease. Patients with these chronic conditions have a higher incidence of various cancers, more aggressive tumors, and a higher mortality rate. It has been proposed that obesity, inflammation and chronic disease should be correlated with cancer at the molecular level, but common gene signatures or networks have yet to be described. Here, we identify genes regulated during the process of cellular transformation in both a breast epithelial cell line and a set of isogenic fibroblastic cell lines. The resulting gene signature strongly mimics those of many different cancer types, thereby validating these experimental systems as models of oncogenesis. Furthermore, it uncovers transcriptional factors and common gene regulatory networks linking cancer with other disease states such as atheroscelorsis, type II diabetes, obesity, lupus, and cardiomyopathy. We suggest that this common transcriptional program can contribute to the concurrence of different diseases, and that the interplay between this program and cell-type specific factors can give rise to a variety of human diseases. Two isogenic cell lines were used to model transformation. The first employed an inducible oncogene: src fused to the ligand binding domain of the estrogen receptor. ER-src and pBABE control cells were dosed with Tamoxifen or Etoh control across several time points to monitor gene expression during transformation. The other model consists of three isogenic cell lines derived from primary fibroblasts in a serial manner. The first is immortalized by overexpression of telomerase (hTERT), and exhibits normal fibroblast morphology. The second expresses hTERT along with both large and small T antigens of Simian virus 40, and it displays an altered morphology but is not transformed. The third cell line expresses hTERT, T antigens, and an oncogenic derivative of Ras (H-RasV12); it is morphologically transformed and has tumorigenic potential in soft agar and nude mice. Thus, three stages of transformation are represented by these cells.

ORGANISM(S): Homo sapiens

SUBMITTER: Kevin Struhl

PROVIDER: E-GEOD-17941 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

A transcriptional signature and common gene networks link cancer with lipid metabolism and diverse human diseases.

Hirsch Heather A HA Iliopoulos Dimitrios D Joshi Amita A Zhang Yong Y Jaeger Savina A SA Bulyk Martha M Tsichlis Philip N PN Shirley Liu X X Struhl Kevin K

Cancer cell 20100401 4

Transcriptional profiling of two isogenic models of transformation identifies a gene signature linking cancer with inflammatory and metabolic diseases. In accord with this common transcriptional program, many drugs used for treatment of diabetes and cardiovascular diseases inhibit transformation and tumor growth. Unexpectedly, lipid metabolism genes are important for transformation and are upregulated in cancer tissues. As in atherosclerosis, oxidized LDL and its receptor OLR1 activate the infla ...[more]

PMID: 20385360

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Project description:Ovarian estrogen (E2) and progesterone (P4) are indispensable for embryo-implantation and endometrial stromal decidualization; however, the molecular mechanisms that underpin these reproductive processes are unclear. Steroid receptor coregulator-2 (SRC-2) belongs to the multifunctional SRC/p160 family which also includes SRC-1 and SRC-3. Sharing strong sequence homology, all three SRCs exert diverse regulatory effects by modulating the transcriptional potency of nuclear receptor family members, including the estrogen and progesterone receptor (ER and PR respectively). Importantly, absence of SRC-2 in PR positive cells in the epithelial, stromal, and myometrial compartments of the murine uterus results in a striking infertility defect. This reproductive phenotype highlights a key role for SRC-2 in uterine function which is not shared with other coregulators. Intriguingly, abrogation of uterine SRC-2 does not block embryo apposition or attachment to the apical surface of luminal epithelial cells of the endometrium but rather prevents P4-dependent local decidualization of the sub-epithelial stroma. Remarkably, epithelial-specific ablation of SRC-2 in the murine uterus does not compromise endometrial functionality, again underscoring the unique importance of stromal derived SRC-2 in uterine function. The stromal decidualization defect resulting from SRC-2 ablation is reflected at the molecular level by a marked attenuation in P4 responsive target genes known to be critical for P4 dependent decidualization (i.e. ERBB receptor feedback inhibitor 1, Follistatin and Fkbp5). Conversely, the induction of E2 or P4 target genes involved in embryo implantation (i.e. leukemia inhibitory factor (LIF) and Indian hedgehog (Ihh) respectively) is not affected by SRC-2’s absence. As with mouse studies, decidualization of primary human stromal cells (HESCs) in culture is blocked by SRC-2 knockdown; however, HESC decidualization is unaffected by knockdown of SRC-1 or SRC-3. As a consequence of SRC-2 knockdown, molecular studies disclose a striking decrease in the induction of a subset of P4 target genes (i.e. WNT4 and FKBP5) which are essential for the stromal-epithelioid transformation step, the cellular hallmark of endometrial decidualization. Collectively, these studies not only showcase the evolutionary importance of SRC-2 in endometrial biology but also suggest that deregulation of this coregulator may underpin a spectrum of hormone-dependent uterine pathologies such as endometriosis and endometrial cancer. Microarray analysis was performed on mouse uteri using eighteen SRC-2flox/flox (SRC-2f/f) and eighteen PRCre/+ SRC-2flox/flox (SRC-2d/d) mice. Mice were ovariectomized at 6 weeks and after 2 weeks mice were either treated with sesame oil (vehicle) or 1 mg of P4. RNA from three mice per genotype per treatment were pooled and assigned as one sample (three samples per genotype per treatment). multiple group comparison

Dataset Information

A Transcriptional Signature and Common Gene Networks Link Cancer with Metabolic Syndrome and Auto-immune Diseases

Publications

A transcriptional signature and common gene networks link cancer with lipid metabolism and diverse human diseases.

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