Crosstalk between Adiponectin and IGF-IR in breast cancer. Prof. Young Jin Suh Department of Surgery The Catholic University of Korea

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1 Crosstalk between Adiponectin and IGF-IR in breast cancer Prof. Young Jin Suh Department of Surgery The Catholic University of Korea

2 Obesity Chronic, multifactorial disorder Hypertrophy and hyperplasia of adipocytes Related to many metabolic disorders Associated with increased cancer risk Adipose tissue: storage reservoir or endocrine organ Adiponectin 1/body mass index LOW adiponectin and IGF-I/IGF-IR signaling IGF-I: insulin-like growth factor IGF-IR: IGF-I receptor

3 Role of obesity/adipose tissue In breast cancer risk or tumor phenotype controversial Only by increased estrogen production? Adipocytokines(adipocyte-derived factors) may contribute to regulation of development and progression J Mammary Gland Biol Neoplasia 2013;18: Adiponectin: synthesized almost by adipose tissue, plasma conc. inversely correlated with adiposity Endocr Rev 2005;26: J Clin Endocrinol Metab 2001;86: Conc. - concentration

4 Adiponectin Anti-inflammatory activity Protective against metabolic disorders, such as insulin resistance, fatty acid oxidation and insulin sensitivity When reduced, risk factor for type II DM, CVD and several cancers J Clin Endocrinol Metab 2004;89: Clin Cancer Res 2003;9: Anti-proliferative in ERα(-), not in ERα(+) Br J Cancer 2008;98: Arch Pharm Res 2005;28: DM diabetes, CVD cardiovascular diseases

5 Obesity & Breast Carcinogenesis Serious risk factor, positively correlated with poor outcome Cancer Epidemiol Biomarkers Prev 2005;14: Obesity-greater aromatase activity- estrogen production : Not enough Estrogen-independent mechanism with insulin resistance, hyperinsulinemia, bioavailable IGF-I, dysregulation of IGF-IR pathway. J Carcinog 2013;12:19 Adipokines recruit macrophage that release proinflammatory molecules, which contribute insulin resistance and breast cancer tumorigenesis Oncologist 2010;15: Clin Cancer Res 2013;19:

6 Adiponectin Produced exclusively in white adipocytes Gene on chromosome 3q27 Plasma level(3~30 μg / ml )-Inversely correlated with BMI, lower in the obese J Mammary Gland Biol Neoplasia 2013;18: Mol Cell Endocrinol 2010;316: Mechanism of down regulation - unclear by proinflammatory cytokines(tnfα)? Nat Rev Immunol 2006;6: BMI body mass index

7 Adiponectin Receptors AdipoR1 Diabetes 2004;53: high affinity for globular adiponectin - abundantly in endothelial cells AdipoR2 Med Oncol 2011;28: Predominantly in the liver T-cadherin: non-classical receptor - mediating functional effect? - co-receptor? Biochemistry 2008;47: AdipoR adiponectin receptor

8 Adiponectin Signaling Adaptor (binding) protein APPL1 Cancer Biol Med 2012;9: Effective through AMPK, mtor, PI3K/Akt, MAPK, PPAR-α, STAT3, NF-kB Mostly through AMPK(cellular energy sensor) fatty acid oxidation, glucose uptake, gluconeogenesis Insulin-sensitizing through PPAR-α results in insulin sensitivity in vivo Diabetes 2003;52: Nat Med 2001;7:941-6.

9 Adiponectin & Breast Cancer Adiponectin obesity related cancer Endocr Rev 2012;33: Low adiponectin more aggressive breast cancer, by epidemiological studies J Clin Endocrinol Metab 2004;89: Down-regulation of adiponectin and lipid metabolism ethnic difference of cancer susceptibility BMC Genomics 2015;16:S11

10 Interaction between breast cancer and microenvironment 3 mechanisms of microenvironmental molecules (chemokines, cytokines, GF) 1. Increasing genetic instability of tumor 2. Inducing signaling via tumor-associated receptors thereby controlling gene expression 3. Exerting selective pressure on the cells Nat Rev Endocrinol. 2011;8: J Clin Invest 2011;121: GF growth factor

11 Malignant cell phenotype is regulated by autonomous signals from cancer cells and effects of surrounding stromal cells J Clin Endocrinol Metab 2007;92: Role of adipokines on breast tumorigenesis - Unclear and cell type dependency

12 In ERα(-) breast cancer cells Low adiponectin mediate anti-proliferation through regulating genes in cell cycle(p53, Bax, Bcl-2, c-myc, cyclin D1) Med Oncol 2011;28: Adipokine activate AMPK, which in turn inhibits mtor via tuberous sclerosis complex 2(TSC2), thus counteracting carcinogenesis/ stimulating p21, p53 to apoptosis Trends Pharmacol Sci 2005;26: Circ Res 2005;97:

13 In ERα(+) breast cancer cells: Low adiponectin increases proliferation at both genomic and non-genomic levels with positive regulation of cyclin D1 Clin Cancer Res 2009;15: Cell Cycle 2014;13: FASEB J 2015;29:

14 IGF-IR in Breast Cancer Ubiquitous transmembrane tyrosine kinase structurally similar to IR Regulates proliferation, survival, differentiation, transformation, development maintenance of cancer stem cells, epithelialmesenchymal transition, tumor microenvironment Growth Horm IGF Res 2012;22: Overexpressed in subtypes of breast cancer, when activated, interact with substrates such as IRS and SHC Nat Rev Cancer 2004;4: IR insulin receptor IRS insulin receptor substrates SHC Src-homology-2-containing protein SH2

15 Induces activation of Ras/raf/MAPK and PI3K/Akt signaling contribute to breast carcinogenesis J Biol Chem 1990;265: In hormone-dependent breast cancer, 1 IGF-IR and ERα are co-expressed 2 IGF-I acts with E2 proliferation 3 E2 up-regulates IGF-IR 4 E2 stimulates IRS-1 expression Mol Biol Clin Investig (2015) 22(2): Biochem Biophys Res Commun (2001) 288: E2 - estradiol

16 IGF-IR or IRS-1 increase drug and radio-resistance and favor recurrence Curr Cancer Drug Targets 2008;8: IGF-IR counteracts apoptosis in ERα(+) cells, activating IRS-1/PI3K pathway J Mammary Gland Biol Neoplasia 2000;5: IGF axis validated for developing targeted therapy Cancer Res 2012;72(1):3 12. Front Endocrinol 2014;5:224.

17 Adiponectin and IGF-IR interaction IGF/ IGF-IR: involved in metabolic cellular response to adiponectin Nat Med 2001;7: IGF-IR increases cancer growth through activation of Akt and MAPK Cancer Lett 2003;195: Crosstalk between adiponectin/adipor1 and IGF-IR in breast cancer Cell Cycle 2014;13:

18 Low conc. Adiponectin IGF-IR phosphorylation in ERα(+) breast cancer cells, concomitantly with ligandindependent activation of ER α. In MCF-7 cells, upon adiponectin Tx.: knockdown of ERα reduces IGF-IR phosphorylation, whereas sirna for IGF-IR prevents adiponectin-induced ERα transactivation Cell Cycle 2014;13: Conc concentration Tx - treatment

19 IGF-IR plays on formation of protein complex in induction of ERα (+) cell growth Adiponectin enhances coimmunoprecipitation of AdipoR1, APPL1, ERα, IGF-IR and c-src in MCF-7 cells This multiprotein complex lead to MAPK activation via c-src, which is abrogated by sirna targeting ERα or IGF-IR

20 In ERα (-) MDA-MB-231 cells: - adiponectin NOT lead to MAPK phosphorylation, but increase AMPK activation, which mediates antiproliferation FASEB J 2015;9: Biochem Biophys Res Commun 2006;345: Adiponectin enhances IRS-1 in ERα (+) breast cancer cells, amplifying IGF/IGF-IR growth signaling

21 Frontiers in Oncology 2015:5:157

22 Conclusion Adiponectin emerging crucial adipokine in breast carcinogenesis in obese women Interaction with receptors activates multiple pathways through interplay between ERα and IGF-IR This leads to 1) Increased MAPK activation, upregulation of genes involved in proliferation and inhibition of apoptosis 2) Induction of cell migration Antagonistic effects by adiponectin on IGF-IR signaling ONLY on ERα(-) breast cancer cells