Transcriptional activity of ATF3 in the stromal compartment of tumors promotes cancer progression

Buganim, Yosef; Madar, Shalom; Rais, Yoach; Pomeraniec, Leslie; Harel, Einav; Solomon, Hilla; Kalo, Eyal; Goldstein, Ido; Brosh, Ran; Haimov, Ora; Avivi, Camila; Polak‐Charcon, Sylvie; Goldfinger, Naomi; Barshack, Iris; Rotter, Varda

doi:10.1093/carcin/bgr203

Cited by 41 publications

(33 citation statements)

References 43 publications

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“…In a previous study, ATF3 protein levels were greatly increased in cells treated with arsenite for 4-6 h but were undetectable in untreated control cells (Fawcett et al, 1999). These reports indicate that cells that lack OGG1 function and the transcriptional activity of ATF3 in neoplastic transformation are a novel promoter and a potential target for anticancer therapy (Buganim et al, 2011).…”

Section: Discussionmentioning

confidence: 73%

Roles of oxidative stress and the ERK1/2, PTEN and p70S6K signaling pathways in arsenite-induced autophagy

Huang

Chai

2015

Toxicology Letters

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Section: Discussionmentioning

confidence: 73%

Roles of oxidative stress and the ERK1/2, PTEN and p70S6K signaling pathways in arsenite-induced autophagy

Huang

Chai

2015

Toxicology Letters

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“…The prototypical basic region-leucine zipper (bZip) protein, c-JUN is expressed in human atherosclerotic plaques and promotes SMC proliferation and neointima formation in vivo [34]. ATF3 is another stress-inducible gene upregulated in many cancers [35] and also in SMCs within injured mouse femoral arteries, to promote SMC migration and ECM synthesis [36]. It has been shown that c-Jun readily forms heterodimers with ATF2 and ATF3, which have distinct DNA binding affinities to CRE and AP-1 elements [37].…”

Section: Discussionmentioning

confidence: 99%

Disease-Related Growth Factor and Embryonic Signaling Pathways Modulate an Enhancer of TCF21 Expression at the 6q23.2 Coronary Heart Disease Locus

et al. 2013

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Coronary heart disease (CHD) is the leading cause of mortality in both developed and developing countries worldwide. Genome-wide association studies (GWAS) have now identified 46 independent susceptibility loci for CHD, however, the biological and disease-relevant mechanisms for these associations remain elusive. The large-scale meta-analysis of GWAS recently identified in Caucasians a CHD-associated locus at chromosome 6q23.2, a region containing the transcription factor TCF21 gene. TCF21 (Capsulin/Pod1/Epicardin) is a member of the basic-helix-loop-helix (bHLH) transcription factor family, and regulates cell fate decisions and differentiation in the developing coronary vasculature. Herein, we characterize a cis-regulatory mechanism by which the lead polymorphism rs12190287 disrupts an atypical activator protein 1 (AP-1) element, as demonstrated by allele-specific transcriptional regulation, transcription factor binding, and chromatin organization, leading to altered TCF21 expression. Further, this element is shown to mediate signaling through platelet-derived growth factor receptor beta (PDGFR-β) and Wilms tumor 1 (WT1) pathways. A second disease allele identified in East Asians also appears to disrupt an AP-1-like element. Thus, both disease-related growth factor and embryonic signaling pathways may regulate CHD risk through two independent alleles at TCF21.

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“…CAFs #1 cells were derived from a lung metastasis of breast cancer and were immortalized by human telomerase reverse transcriptase (hTERT), as described previously [78]. CAFs #2 cells were derived from a primary breast tumor of a different patient and were kept in culture without hTERT immortalization.…”

Section: Methodsmentioning

confidence: 99%

Regulation of the inflammatory profile of stromal cells in human breast cancer: prominent roles for TNF-α and the NF-κB pathway

et al. 2015

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IntroductionBreast cancer progression is promoted by stromal cells that populate the tumors, including cancer-associated fibroblasts (CAFs) and mesenchymal stem/stromal cells (MSCs). The activities of CAFs and MSCs in breast cancer are integrated within an intimate inflammatory tumor microenvironment (TME) that includes high levels of tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). Here, we identified the impact of TNF-α and IL-1β on the inflammatory phenotype of CAFs and MSCs by determining the expression of inflammatory chemokines that are well-characterized as pro-tumorigenic in breast cancer: CCL2 (MCP-1), CXCL8 (IL-8) and CCL5 (RANTES).MethodsChemokine expression was determined in breast cancer patient-derived CAFs by ELISA and in patient biopsies by immunohistochemistry. Chemokine levels were determined by ELISA in (1) human bone marrow-derived MSCs stimulated by tumor conditioned media (Tumor CM) of breast tumor cells (MDA-MB-231 and MCF-7) at the end of MSC-to-CAF-conversion process; (2) Tumor CM-derived CAFs, patient CAFs and MSCs stimulated by TNF-α (and IL-1β). The roles of AP-1 and NF-κB in chemokine secretion were analyzed by Western blotting and by siRNAs to c-Jun and p65, respectively. Migration of monocytic cells was determined in modified Boyden chambers.ResultsTNF-α (and IL-1β) induced the release of CCL2, CXCL8 and CCL5 by MSCs and CAFs generated by prolonged stimulation of MSCs with Tumor CM of MDA-MB-231 and MCF-7 cells. Patient-derived CAFs expressed CCL2 and CXCL8, and secreted CCL5 following TNF-α (and IL-1β) stimulation. CCL2 was expressed in CAFs residing in proximity to breast tumor cells in biopsies of patients diagnosed with invasive ductal carcinoma. CCL2 release by TNF-α-stimulated MSCs was mediated by TNF-RI and TNF-RII, through the NF-κB but not via the AP-1 pathway. Exposure of MSCs to TNF-α led to potent CCL2-induced migration of monocytic cells, a process that may yield pro-cancerous myeloid infiltrates in breast tumors.ConclusionsOur novel results emphasize the important roles of inflammation-stroma interactions in breast cancer, and suggest that NF-κB may be a potential target for inhibition in tumor-adjacent stromal cells, enabling improved tumor control in inflammation-driven malignancies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0080-7) contains supplementary material, which is available to authorized users.

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Transcriptional activity of ATF3 in the stromal compartment of tumors promotes cancer progression

Cited by 41 publications

References 43 publications

Roles of oxidative stress and the ERK1/2, PTEN and p70S6K signaling pathways in arsenite-induced autophagy

Roles of oxidative stress and the ERK1/2, PTEN and p70S6K signaling pathways in arsenite-induced autophagy

Disease-Related Growth Factor and Embryonic Signaling Pathways Modulate an Enhancer of TCF21 Expression at the 6q23.2 Coronary Heart Disease Locus

Regulation of the inflammatory profile of stromal cells in human breast cancer: prominent roles for TNF-α and the NF-κB pathway

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