Pharmacology and Therapeutics - Theses

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    The impact of Resolvin D2 on breast tumour growth and spread
    Al-Zaubai, Nuha ( 2015)
    Epidemiological and experimental data suggest a close connection between inflammation and tumorigenesis. A role for inflammation in tumorigenesis is now generally accepted,andithasbecome evident that an inflammatory microenvironment is an essential component of all tumours, including some in which a direct causal relationship with inflammation is not yet proven. Only a minority of all cancers are caused by germline mutations, whereas the vast majority (90%) are linked to somatic mutations and environmental factors. Many environmental causes of cancer and risk factors, including chronic infections, tobacco smoking, inhaled pollutants, increased age and obesity are associated with some forms of chronic inflammation. Resolution of inflammation, previously thought to take place passively, is now considered an active process that enables the inflamed tissues to return to homeostasis. Resolution is initiated by specialized pro-resolving mediators that are biosynthesized locally. These mediator include lipoxins, resolvins, protectins and maresins. Although the role of pro-inflammatory mediators in carcinogenesis has become more and more evident and well characterized,thepotentialroleofpro-resolvingmediators in this process remains still elusive. Our laboratory has identified several inflammation-resolving mediators such as annexin A1 and lipoxin A4 as mitogens for breast cancer cells, mediating their effects via formyl peptide receptors. Resolvin D2 (RvD2) is a potent anti-inflammatory/pro-resolving tri- hydroxy lipid mediator generated endogenously from the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA). As RvD2 may be synthesized within breast tumours by both breast tumour and the surrounding stroma cells (enzymes involved in its synthesis expressed in both cell types), we have characterized the impact of RvD2 on tumour cell processes underlying breast tumour growth and spread. Data presented within this thesis has provided the first evidence that RvD2 has the potential to function as a modulator of ERα signalling in ER-positive breast cancer cells. Resolvin D2 was shown topromotetheproliferationoftheER-positive,MCF-7,butnottheER-negative,MDA-MB-231,breast cancer cells. 17β-estradiol and resolvin D2 were also shown to inhibit transforming growth factor β-induced epithelial-mesenchymal transition and invasiveness of MCF-7 cells. These effects were completely inhibited by the estrogen receptor antagonist ICI 182,780. The inhibitory effect of RvD2 on interleukin-6 and -8 release from MCF-7 cells was also ERα-dependent. Evidence was also presented that RvD2 has the potential to inhibit macrophage recruitment by breast tumour cells by inhibiting the production of the chemoattractant, colony stimulating factor-1 and monocyte chemoattractant protein- 1. The studies presented in this thesis have led to an increased appreciation of the potential influences of the inflammation-resolving mediators, RvD2 in particular, on breast tumorigenesis. Our view suggests that further research into the pro-resolving signal transduction pathways and their regulators is essential to ultimately harnessing these pathways into therapeutic gain in numerous disease contexts including cancer.