Expression and responsiveness of cytokines and their receptors in breast cancer

Abstract

Chronic inflammation is a critical component in breast cancer progression. Pro-inflammatory mediators along with growth/survival factors within the tumor microenvironment potentiate enhanced expression of pro-inflammatory cytokines (IL-1, IL-6, TNF-alpha), chemotactic cytokines and their receptors (CXCR4, CXCL12, CXCL8) and angiogenic factors (VEGF) that often overcome the function of anti-inflammatory molecules (IL-4, IL-10) eradicating the host's anti-tumor immunity. Therefore detailed knowledge of the regulatory mechanisms determining cytokine levels is essential to understand the pathogenesis of several diseases including breast cancer. Activated transcription factors such as NF-kappaB and HIF-1alpha are important players for the establishment of a pro-inflammatory and potentially oncogenic environment. HIF-1alpha 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 which induces apoptosis or cell cycle arrest in neoplastic cells. Functional crosstalk between HIF-1alpha and p53 pathways mediated by co-regulators shared between the two transcription factors such as SRC-1 and SIRT-1 differentially regulate diverse subsets of target gene expression under variable stress conditions. In an attempt to shed light in the complex regulatory mechanisms involved in cancer related inflammation, we investigated the effect of the chemotherapeutic drug etoposide, which induces p53, on the expression of inflammatory genes (CXCR4, TNF-alpha, IL-10) carrying hypoxia responsive elements within the regulatory regions of their promoters in breast cancer cells under hypoxia mimicking conditions. In addition, the role of two common p53 and HIF-1alpha co-regulators, namely SRC-1 and SIRT-1, in the expression of the highly potent metastatic chemokine receptor CXCR4 was evaluated. 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.

Date of Award	3 Jan 2012
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Marija Krstic-Demonacos (Supervisor) & Costas Demonacos (Supervisor)