Regulation of CXCR4 gene expression in breast cancer cells under diverse stress conditions

Andreou,Kleopatra; Rajendran,Ramkumar; Krstic-Demonacos,Marija; Demonacos,Constantinos

doi:10.3892/ijo.2012.1643

Regulation of CXCR4 gene expression in breast cancer cells under diverse stress conditions

Authors:
- Kleopatra Andreou
- Ramkumar Rajendran
- Marija Krstic-Demonacos
- Constantinos Demonacos
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Affiliations: School of Pharmacy and Pharmaceutical Sciences, Stopford Building, University of Manchester, Manchester, M13 9PT, UK, Faculty of Life Sciences, Michael Smith Building, University of Manchester, Manchester, M13 9PT, UK
Published online on: September 27, 2012 https://doi.org/10.3892/ijo.2012.1643
Pages: 2253-2259

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Abstract

Chronic inflammation is a critical component in breast cancer progression. Pro-inflammatory mediators along with growth/survival factors within the tumor microenvironment potentiate the expression of pro-inflammatory cytokines (IL-1, IL-6, TNF-α), chemotactic cytokines and their receptors (CXCR4, CXCL12, CXCL8) and angiogenic factors (VEGF) that often overcome the effect of anti-inflammatory molecules (IL-4, IL-10) thus evading the host's antitumor immunity. Detailed knowledge, therefore, of the regulatory mechanisms determining cytokine levels is essential to understand the pathogenesis of breast cancer. HIF-1α and NF-κB transcription factors are important players for the establishment of a pro-inflammatory and potentially oncogenic environment. HIF-1α is the key mediator of the cellular response to oxygen deprivation and induces the expression of genes involved in survival and angiogenesis within solid hypoxic tumors. The expression of these genes is often modulated by the p53 tumor suppressor protein that induces apoptosis or cell cycle arrest in neoplastic cells. Functional crosstalk between HIF-1α and p53 pathways mediated by modulators shared between the two transcription factors such as SRC-1 and SIRT-1 differentially regulate the expression of distinct subsets of their target genes under variable stress conditions. In an attempt to shed light on the complex regulatory mechanisms involved in cancer-related inflammation, we investigated the role of the two common p53 and HIF-1α co-regulators SRC-1 and SIRT-1, in the expression of the highly potent metastatic chemokine receptor CXCR4. Both SRC-1 and SIRT-1 overexpression in DSFX-treated MCF-7 cells reduced CXCR4 cellular levels implying that both co-regulators are crucial factors in the determination of the metastatic potential of breast cancer cells.

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