Crosstalk between Adiponectin and IGF-IR in breast cancer Prof. Young Jin Suh Department of Surgery The Catholic University of Korea
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
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;18:321-32. Adiponectin: synthesized almost by adipose tissue, plasma conc. inversely correlated with adiposity Endocr Rev 2005;26:439-51 J Clin Endocrinol Metab 2001;86:1930-5. Conc. - concentration
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;89:1102-7. Clin Cancer Res 2003;9:5699-704. Anti-proliferative in ERα(-), not in ERα(+) Br J Cancer 2008;98:370-9. Arch Pharm Res 2005;28:1263-9. DM diabetes, CVD cardiovascular diseases
Obesity & Breast Carcinogenesis Serious risk factor, positively correlated with poor outcome Cancer Epidemiol Biomarkers Prev 2005;14:1686-91. 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;15:556-65. Clin Cancer Res 2013;19:6074-83.
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;18:321-32. Mol Cell Endocrinol 2010;316:129-39. Mechanism of down regulation - unclear by proinflammatory cytokines(tnfα)? Nat Rev Immunol 2006;6:772-83. BMI body mass index
Adiponectin Receptors AdipoR1 Diabetes 2004;53:2132-6. - high affinity for globular adiponectin - abundantly in endothelial cells AdipoR2 Med Oncol 2011;28:1288-95. - Predominantly in the liver T-cadherin: non-classical receptor - mediating functional effect? - co-receptor? Biochemistry 2008;47:11682-92. AdipoR adiponectin receptor
Adiponectin Signaling Adaptor (binding) protein APPL1 Cancer Biol Med 2012;9:213-20. 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;52:1355-63. Nat Med 2001;7:941-6.
Adiponectin & Breast Cancer Adiponectin obesity related cancer Endocr Rev 2012;33:547-94. Low adiponectin more aggressive breast cancer, by epidemiological studies J Clin Endocrinol Metab 2004;89:1102-7. Down-regulation of adiponectin and lipid metabolism ethnic difference of cancer susceptibility BMC Genomics 2015;16:S11
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;8:263 75. J Clin Invest 2011;121:3804 9. GF growth factor
Malignant cell phenotype is regulated by autonomous signals from cancer cells and effects of surrounding stromal cells J Clin Endocrinol Metab 2007;92:1041 8. Role of adipokines on breast tumorigenesis - Unclear and cell type dependency
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;28:1288 95. 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;26:69 76. Circ Res 2005;97:837 44.
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;15:3265 76. Cell Cycle 2014;13:553 64. FASEB J 2015;29:2150 60.
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;22:193 9. Overexpressed in subtypes of breast cancer, when activated, interact with substrates such as IRS and SHC Nat Rev Cancer 2004;4:505 18. IR insulin receptor IRS insulin receptor substrates SHC Src-homology-2-containing protein SH2
Induces activation of Ras/raf/MAPK and PI3K/Akt signaling contribute to breast carcinogenesis J Biol Chem 1990;265:21172 8. 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):53 62. Biochem Biophys Res Commun (2001) 288:685 9. E2 - estradiol
IGF-IR or IRS-1 increase drug and radio-resistance and favor recurrence Curr Cancer Drug Targets 2008;8:597 610. IGF-IR counteracts apoptosis in ERα(+) cells, activating IRS-1/PI3K pathway J Mammary Gland Biol Neoplasia 2000;5:95 105. IGF axis validated for developing targeted therapy Cancer Res 2012;72(1):3 12. Front Endocrinol 2014;5:224.
Adiponectin and IGF-IR interaction IGF/ IGF-IR: involved in metabolic cellular response to adiponectin Nat Med 2001;7:941 6. IGF-IR increases cancer growth through activation of Akt and MAPK Cancer Lett 2003;195:127 37. Crosstalk between adiponectin/adipor1 and IGF-IR in breast cancer Cell Cycle 2014;13:553 64.
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;13:553 64. Conc concentration Tx - treatment
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
In ERα (-) MDA-MB-231 cells: - adiponectin NOT lead to MAPK phosphorylation, but increase AMPK activation, which mediates antiproliferation FASEB J 2015;9:2150 60. Biochem Biophys Res Commun 2006;345:271 9. Adiponectin enhances IRS-1 in ERα (+) breast cancer cells, amplifying IGF/IGF-IR growth signaling
Frontiers in Oncology 2015:5:157
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