Wang Y, Lam JB, Lam KS, Liu J, Lam MC, Hoo RL, Wu D, Cooper GJ, Xu AAdiponectin modulates the glycogen synthase kinase-3beta/beta-catenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude mice. Cancer Res 66: 11462-11470

Genome Research Center, University of Hong Kong, China.
Cancer Research (Impact Factor: 9.33). 01/2007; 66(23):11462-70. DOI: 10.1158/0008-5472.CAN-06-1969
Source: PubMed


Adiponectin is an adipokine that has pleiotropic beneficial roles in systemic insulin resistance and inflammation. Several recent clinical studies suggest that low serum levels of adiponectin are associated with increased risks of breast cancer. Here, we investigated the direct effects of adiponectin on breast cancer development in vitro and in vivo. Our results showed that adiponectin significantly attenuated the proliferations of two typical human breast cancer cells, MDA-MB-231 and T47D, in a cell type-specific manner. Further analysis revealed that adiponectin could induce apoptosis and arrest the cell cycle progression at G(0)-G(1) phase in MDA-MB-231 cells. Prolonged treatment with adiponectin in this cell line blocked serum-induced phosphorylation of Akt and glycogen synthase kinase-3beta (GSK-3beta), suppressed intracellular accumulation of beta-catenin and its nuclear activities, and consequently reduced expression of cyclin D1. Adiponectin-mediated suppression of cyclin D1 expression and attenuation of cell proliferation was abrogated by the GSK-3beta inhibitor lithium chloride. These results suggest that the inhibitory role of adiponectin on MDA-MB-231 cell growth might be attributed to its suppressive effects on the GSK-3beta/beta-catenin signaling pathway. Furthermore, our in vivo study showed that both supplementation of recombinant adiponectin and adenovirus-mediated overexpression of this adipokine substantially reduced the mammary tumorigenesis of MDA-MB-231 cells in female nude mice. Taken together, these data support the role of adiponectin as a negative regulator of breast cancer development and also suggest that adiponectin might represent a novel therapeutic target for this disease.

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    • "Adiponectin is considered as a protective hormone, as it plays a major role in the regulation of glucose with potent insulin-sensitizing activity affecting the uptake of glucose in the muscle, in lipid homeostasis, and is involved in the pathophysiology of atherosclerosis with anti-inflammatory activity [7]. Numerous studies have shown an inhibitory activity of adiponectin on the proliferation of various cell types, including aortic smooth muscle cells, endothelial cells, and several types of cancer cells [8–10]. In previous epidemiologic studies investigating associations between adiponectin and breast cancer, investigators have assumed that blood adiponectin concentrations are good surrogates of tissue exposure. "
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    ABSTRACT: Published results suggests that high adiponectin level may decrease the risk of breast cancer. However, available evidence on breast cancer is conflicting. Therefore a meta-analysis was performed to assess the association between blood adiponectin and breast cancer risk. PubMed database, Web of Science, Elsevier Science, Springer Link and bibliographies of retrieved articles were searched for epidemiological studies published up to March 2013. Meta-analysis was performed on the combined effect values (OR) as well as standardized mean difference (SMD) including 17 studies. Fixed or random effect pooled measure was selected on the basis of homogeneity test among studies. The publication bias was assessed by the Egger's regression asymmetry test and Begg's rank correlation test with Begg's funnel plot. Subgroup analyses and sensitivity analysis were also performed. A total of 13 studies involving 3578 breast cancer cases and 4363 controls contributed to the OR analysis. The high adiponectin level did not significantly affect breast cancer risk (OR=0.902, 95% CI=0.773-1.053). After excluding articles that were the key contributors to between-study heterogeneity, the OR of high adiponectin level was associated with decreased breast cancer risk (OR=0.838, 95% CI=0.744-0.943). There was a significantly association between high adiponectin level and postmenopausal breast cancer women (OR=0.752, 95%CI=0.604-0.936); and it was not associated with premenopausal breast cancer women (OR=0.895, 95%CI=0.638-1.256). The result of pooled measure on SMD was that the high adiponectin level was associated with decreased breast cancer risk (SMD= -0.348, 95% CI= -0.533--0.614) after excluding articles which were the key contributors to between-study heterogeneity. Our findings indicate that high adiponectin level might decrease the risk of postmenopausal breast cancer. More randomized clinical trials and observational studies are needed to confirm this association with underlying biological mechanisms in the future.
    PLoS ONE 08/2013; 8(8):e73183. DOI:10.1371/journal.pone.0073183 · 3.23 Impact Factor
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    • "In vitro assays studying the effects of leptin and adiponectin on cell proliferation have found a stimulatory role of leptin and an inhibitory role of adiponectin in mammary tumor growth [27]–[29]. These observations suggest that leptin and adiponectin exert procarcinogenic and anticarcinogenic effects, respectively. "
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    ABSTRACT: Obesity is now considered as a risk factor for breast cancer in postmenopausal women. Adipokine levels are modulated in obesity, and may play a role in carcinogenesis. Moreover, obesity increases risk of cancer mortality. Here, we hypothesized that this increase could be due to a modification in angiogenesis, capital event in the development of metastases, and/or in effectiveness of cancer treatments. To test these assumptions, following a same experimental design and simultaneously the effects of leptin and adiponectin on angiogenesis were investigated, and the impact of hyperleptinemia on anticancer drug effectiveness was measured in physiological and obesity situations. Focusing on angiogenesis, the proliferation of endothelial cells (HUVEC), which expressed leptin and adiponectin receptors, was stimulated by leptin and inhibited by adiponectin. Both adipokines globally reduced apoptosis and caspase activity. Leptin increased migration whereas adiponectin decreased migration, and leptin enhanced the area of the tubes formed by HUVEC cells while adiponectin inhibited their formation. MCF7 and MDA-MB-231 cells treated with leptin secreted more VEGF than untreated cells, whereas adiponectin treatment inhibited VEGF secretion. Finally, MCF7 cells pre-treated with leptin were more invasive than untreated cells. This effect was not reproduced in MDA-MB-231 cells. In the MCF7 breast cancer cell line, leptin could induce cell proliferation and reduced the efficacy of all breast cancer therapies (tamoxifen, 5-fluorouracil, taxol and vinblastin). These results suggest that, in obesity situation, leptin- in contrast to adiponectin - may promote tumor invasion and angiogenesis, leading to metastases 'apparition, and reduce treatment efficacy, which could explain the increased risk of cancer mortality in cases of overweight. The evidence suggests adipokines influence breast cancer issue and could play a significant role, especially in obese patients for which hyperleptinemia, hypoadiponectinemia and increased metastatic potential are described.
    PLoS ONE 03/2013; 8(3):e58541. DOI:10.1371/journal.pone.0058541 · 3.23 Impact Factor
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    • "It is also suggested that tumors arising in patients with low-serum adiponectin levels may have a more aggressive phenotype (large size of tumor, high histologic grade, and increased metastasis) [47] [48]. Providing molecular evidence, several recent studies show adiponectin-mediated antiproliferative response in breast cancer cells [49] [50] [51] [52] [53]. Investigating upstream regulatory nodes capable of orchestrating the downstream signaling axes of adiponectin, we recently show that adiponectin inhibits metastatic properties of breast cancer through activation of master upstream kinase and tumor suppressor, LKB1 [54]. "
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    ABSTRACT: The molecular effects of obesity are mediated by alterations in the levels of adipocytokines. High leptin level associated with obese state is a major cause of breast cancer progression and metastasis, whereas adiponectin is considered a "guardian angel adipocytokine" for its protective role against various obesity-related pathogenesis including breast cancer. In the present study, investigating the role of adiponectin as a potential inhibitor of leptin, we show that adiponectin treatment inhibits leptin-induced clonogenicity and anchorage-independent growth. Leptin-stimulated migration and invasion of breast cancer cells is also effectively inhibited by adiponectin. Analyses of the underlying molecular mechanisms reveal that adiponectin suppresses activation of two canonical signaling molecules of leptin signaling axis: extracellular signal-regulated kinase (ERK) and Akt. Pretreatment of breast cancer cells with adiponectin protects against leptin-induced activation of ERK and Akt. Adiponectin increases expression and activity of the physiological inhibitor of leptin signaling, protein tyrosine phosphatase 1B (PTP1B), which is found to be integral to leptin-antagonist function of adiponectin. Inhibition of PTP1B blocks adiponectin-mediated inhibition of leptin-induced breast cancer growth. Our in vivo studies show that adenovirus-mediated adiponectin treatment substantially reduces leptin-induced mammary tumorigenesis in nude mice. Exploring therapeutic strategies, we demonstrate that treatment of breast cancer cells with rosiglitazone results in increased adiponectin expression and inhibition of migration and invasion. Rosiglitazone treatment also inhibits leptin-induced growth of breast cancer cells. Taken together, these data show that adiponectin treatment can inhibit the oncogenic actions of leptin through blocking its downstream signaling molecules and raising adiponectin levels could be a rational therapeutic strategy for breast carcinoma in obese patients with high leptin levels.
    Neoplasia (New York, N.Y.) 01/2013; 15(1):23-38. DOI:10.1593/neo.121502 · 4.25 Impact Factor
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