Analysis of cytokine expression in breast cancer

Introduction: It has long been recognized that cancer develops in sites of chronic inflammation. Tumours seem to seize molecular pathways seen in wound healing and the inflammatory response and as a consequence appear as "wounds that do not heal". However, the underlying molecular mechanisms facilitating the interconnection of inflammation and cancer remain poorly understood. This body of work aims to analyse mediators of inflammatory response and carcinogenesis on a systemic, breast tissue and cellular level in breast cancer. Methods: Circulating levels of CCL5 and TGFbeta1 were measured in breast cancer patients and age matched controls using ELISA. Gene expression levels of CCL5, CCR5, TGFbeta1, TGFbetaRII, CCL2, CCR2, MMP3 and FAP were analysed in corresponding tumour tissue, normal tissue, and isolated tumour and normal stromal cells using RQ-PCR. CCL5, TGFbeta1 and VEGF and menstrual hormones (LH, FSH, Oestradiol, Progesterone) were quantified in serum samples from healthy, premenopausal volunteers. Results: Systemic levels of TGFbeta1 were significantly elevated in breast cancer patients compared to controls. A significant positive correlation between circulating CCL5 and TGFbeta1 was observed, and mirrored at the gene expression level in tumour tissue from the same breast cancer patients. In primary stromal cells a negative correlation was observed between CCL5 and TGFbeta1. CCL5, CCR5, TGFbeta1, MMP3 and FAP expression was significantly higher in tumour compared to normal breast tissue. A significant negative correlation was observed between circulating CCL5, Oestradiol and Progesterone (r= - 0.50, r= - 0.39 respectively, p<0.05). Gene expression levels of CCL5, FAP, VEGF and MMP3 were found to be increased in tumour compared to normal primary stromal fibroblasts. The cytokine TGFbeta1 was found to be decreased in tumour stromal cells. Conclusion: CCL5 expression is elevated in the tumour microenvironment. The data support a role for hormonal control of circulating CCL5 and also highlight a potentially important relationship between CCL5 and TGFbeta1 in breast cancer.

Funder

National Breast Cancer Research Institute

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Attribution-NonCommercial-NoDerivs 3.0 Ireland

cbn

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University of Galway Theses (PhD Theses)