The fat-derived hormone, adiponectin, as a negative regulator of obesity-related breast cancer diseases

Abstract

Recent epidemiological evidence suggests that aberrant adipokine production is associated with increased risk of obesity-related cancers. Adiponectin, an adipocyte-derived hormone, has been shown to elicit beneficial activities against obesity-related medical complications, including cancer. This study uses cellular and animal models to systematically investigate the anti-tumour activities of this adipokine in obesity-related breast cancer diseases. Conditioned media from 3T3-L1 pre-adipocytes (UCM) stimulated growth of MDA-MB-231 human breast cancer cells, whereas conditioned medium from 3T3-L1 adipocytes (DCM) had opposite effects. Furthermore, recombinant forms of visfatin and fatty acid binding protein-4 stimulated, whereas lipocalin2 and adiponectin inhibited MDA-MB-231 cell growth. Adiponectin neutralization completely attenuated DCM-mediated inhibition, whilst adiponectin treatments attenuated UCM-stimulated MDA-MB231 cell growth. These data suggested that adiponectin may represent one of the major adipokines possessing inhibitory effects on breast cancer proliferation. The detailed in vitro and in vivo activities of adiponectin on MDA-MB-231 cell growth were investigated. Physiological concentrations of adiponectin (15 μg∕mL) inhibited basal and serum-stimulated cell proliferation, promoted apoptosis and attenuated cell migration and invasion in MDA-MB-231 cells. Z another human breast cancer cell line, T47D, adiponectin inhibited insulin-mediated but not FBS-mediated cell growth. Furthermore, nude mice implanted with MDA-MB-231 cells showed that adiponectin treatment could significantly attenuate tumour growth. Investigations of the underlying mechanisms involved in adiponectin-mediated anti-tumour activities found adiponectin inhibited phosphorylation of Akt and attenuated activation of the canonical Wnt/glycogen synthase kinase-3β (GSK-3β)∕β-catenin signalling pathways. Adiponectin also stimulated WIF-I gene and protein expression in a time-dependent manner. Over-expression of WIF-I elicited similar inhibitory effects to that observed with adiponectin treatment, including inhibition of cell proliferation, nuclear β-catenin activity, cyclin Dl expression and serum-induced phosphorylation of Akt and GSK-3β in MDA-MB-231 cells. Blockage ofWIF-1 activities significantly attenuated the suppressive effects of adiponectin on MDA-MB-231 cell growth. Furthermore, w vivo studies showed adiponectin treatment substantially enhanced WIF-I expression in MDAMB-231 tumours implanted in nude mice. Finally, an animal model with spontaneous development of mammary tumour was used to evaluate the pathophysiological role of adiponectin deficiency on tumour development. Adiponectin haplodefιcient MMTV-polyomavirus middle T antigen (MMTV/PyVT) transgenic mice were generated in both FVB/N and C57BL/6J genetic backgrounds. These mice showed accelerated tumour onset and development compared with MMTV/PyVT transgenic mice expressing normal levels of adiponectin, suggesting adiponectin could play a protective role against tumour development. Taken together, the results from this thesis collectively suggest that adiponectin possesses anti-tumour activity and may represent a novel therapeutic target for obesity-related cancers. However, a thorough understanding of how adiponectin elicits its anti-tumour activities at the receptor and post-receptor levels needs to be elucidated.