Obesity and breast cancer: Molecular interconnections and potential clinical applications

Oncologist

Volumn 21, Issue 4, 2016, Pages 404-417

  Simone, Valeria ^a   D’Avenia, Morena ^a   Argentiero, Antonella ^a   Felici, Claudia ^a   Rizzo, Francesca Maria ^a   de Pergola, Giovanni ^a   Silvestris, Franco ^a  

^a UNIVERSITY OF BARI   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ADIPOCYTOKINE; ARYLDIALKYLPHOSPHATASE; ARYLESTERASE; ESTROGEN; EVEROLIMUS; EXEMESTANE; GLUTATHIONE TRANSFERASE; JANUS KINASE 2; LETROZOLE; METFORMIN; PHOSPHATIDYLINOSITOL 4,5 BISPHOSPHATE PHOSPHODIESTERASE; PROGESTERONE RECEPTOR; PROSTAGLANDIN E2; REACTIVE OXYGEN METABOLITE; SOMATOMEDIN BINDING PROTEIN 1; SOMATOMEDIN C RECEPTOR; STAT3 PROTEIN; TAMOXIFEN; TUMOR NECROSIS FACTOR ALPHA ANTIBODY; IL6 PROTEIN, HUMAN; INTERLEUKIN 6; MTOR PROTEIN, HUMAN; TARGET OF RAPAMYCIN KINASE; TUMOR NECROSIS FACTOR;

ARTICLE; BREAST CANCER; CELL PROLIFERATION; DISEASE COURSE; DISEASE FREE SURVIVAL; GENE MUTATION; HUMAN; HYPERINSULINEMIA; INFLAMMATION; INSULIN RESISTANCE; LIFESTYLE MODIFICATION; OBESITY; OXIDATIVE STRESS; PHYSICAL ACTIVITY; POSTMENOPAUSE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; RANDOMIZED CONTROLLED TRIAL (TOPIC); RISK FACTOR; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT; BREAST NEOPLASMS; COMPLICATION; FEMALE; GENETICS; PATHOLOGY;

BREAST NEOPLASMS; ESTROGENS; FEMALE; HUMANS; INFLAMMATION; INSULIN RESISTANCE; INTERLEUKIN-6; OBESITY; POSTMENOPAUSE; RISK FACTORS; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES; TUMOR NECROSIS FACTOR-ALPHA;

EID: 84963795083     PISSN: 10837159     EISSN: 1549490X     Source Type: Journal    
DOI: 10.1634/theoncologist.2015-0351     Document Type: Article

References (129)

1. World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington, DC: AICR, 2007.
2. Key TJ, Appleby PN, Reeves GK et al. Body mass index, serum sexhormones, andbreastcancer risk in postmenopausal women. J Natl Cancer Inst 2003; 95:1218-1226.
3. Reeves GK, Pirie K, Beral V et al. Cancer incidence and mortality in relation to body mass index in the Million Women Study: Cohort study. BMJ 2007;335:1134.
4. Renehan AG, Tyson M, Egger M et al. Body-mass index and incidence of cancer: A systematic review and meta-analysis of prospective observational studies. Lancet 2008;371:569-578.
5. Vainio H, Bianchini F, eds. Weight Control and Physical Activity, Vol. 6. IARC Handbook of Cancer Prevention. Lyon, France: IARC Press; 2002:1-315.
6. John EM, Phipps AI, Sangaramoorthy M. Body size, modifying factors, and postmenopausal breast cancer risk in a multiethnic population: The San Francisco BayArea breast cancer study. Springerplus 2013;2:239.
7. Cheraghi Z, Poorolajal J, Hashem T et al. Effect of body mass index on breast cancer during premenopausal and postmenopausal periods: A metaanalysis. PLoS One 2012;7:e51446.
8. Bhaskaran K, Douglas I, Forbes H et al. Bodymass index and risk of 22 specific cancers: A population-based cohort study of 5·24 million UK adults. Lancet 2014;384:755-765.
9. Daling JR, Malone KE, Doody DR. et al. Relation of body mass index to tumor markers and survival among young women with invasive ductal breast carcinoma. Cancer 2001;92:720-729.
10. Olivotto IA, Jackson JS, Mates D et al. Prediction of axillary lymph node involvement of women with invasive breast carcinoma: A multivariate analysis. Cancer 1998;83:948-955.
11. Ewertz M, Jensen MB, Gunnarsdóttir KÁ et al. Effect of obesity on prognosis after early-stage breast cancer. J Clin Oncol 2011;29:25-31.
12. Berclaz G, Li S, Price KN et al. Body mass index as a prognostic feature in operable breast cancer: The International Breast Cancer Study Group experience. Ann Oncol 2004;15:875-884.
13. Chan DSM, Vieira AR, Aune D et al. Body mass index and survival in women with breast cancer—Systematic literature review and metaanalysis of 82 follow-up studies. AnnOncol 2014;25: 1901-1914.
14. Krishnan K, Bassett JK, MacInnis RJ et al. Associations between weight in early adulthood, change in weight, and breast cancer risk in postmenopausal women. Cancer Epidemiol Biomarkers Prev 2013;22:1409-1416.
15. Lukanova A, Lundin E, Zeleniuch-Jacquotte A et al. Body mass index, circulating levels of sexsteroid hormones, IGF-I and IGF-binding protein-3: A cross-sectional study in healthy women. Eur J Endocrinol 2004;150:161-171.
16. Rose DP, Vona-Davis L. Biochemical and molecular mechanisms for the association between obesity, chronic inflammation, and breast cancer. Biofactors 2014;40:1-12.
17. Laplante M, Sabatini DM. mTOR signaling in growthcontroland disease. Cell 2012;149:274-293.
18. Xu F, Zhou G, Han S et al. Association of TNF-a, TNFRSF1A and TNFRSF1B gene polymorphisms with the risk of sporadic breast cancer in northeast Chinese Han women. PLoS One 2014; 9:e101138.
19. Joshi N, Kannan S, Kotian N et al. Interleukin 6 2174G. C polymorphism and cancer risk: Metaanalysis reveals a site dependent differential influence in ancestral North Indians. Hum Immunol 2014;75:901-908.
20. Kirschner MA, Schneider G, Ertel NH et al. Obesity, androgens, estrogens, and cancer risk. Cancer Res 1982;42(suppl):3281s-3285s.
21. Simpson ER, Brown KA. Obesity and breast cancer: Role of inflammation and aromatase. J Mol Endocrinol 2013;51:T51-T59.
22. Morris PG, Hudis CA, Giri D et al. Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer. Cancer Prev Res (Phila) 2011;4:1021-1029.
23. Kern PA, Ranganathan S, Li C et al. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 2001;280:E745-E751.
24. Skurk T, Alberti-Huber C, Herder C et al. Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab 2007;92:1023-1033.
25. Bulun SE, Price TM, Aitken J et al. A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. J Clin Endocrinol Metab 1993;77:1622-1628.
26. Chen D, Reierstad S, Fang F et al. JunD and JunB integrate prostaglandin E2 activation of breast cancer-associated proximal aromatase promoters. Mol Endocrinol 2011;25:767-775.
27. Meng L, Zhou J, Sasano H et al. Tumor necrosis factor alpha and interleukin 11 secreted by malignant breast epithelial cells inhibit adipocyte differentiation by selectively down-regulating CCAAT/ enhancer binding protein alpha and peroxisome proliferator-activated receptor gamma:Mechanism of desmoplastic reaction. Cancer Res 2001;61: 2250-2255.
28. Zhou J, Gurates B, Yang S et al. Malignant breast epithelial cells stimulate aromatase expression viapromoter II inhumanadipose fibroblasts:An epithelial-stromal interaction in breast tumors mediated by CCAAT/enhancer binding protein beta. Cancer Res 2001;61:2328-2334.
29. Mawson A, Lai A, Carroll JS et al. Estrogen and insulin/IGF-1 cooperatively stimulate cell cycle progression in MCF-7 breast cancer cells through differential regulation of c-Myc and cyclin D1. Mol Cell Endocrinol 2005;229:161-173.
30. Lee AV, Jackson JG, Gooch JL et al. Enhancement of insulin-like growth factor signaling in human breast cancer: Estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo. Mol Endocrinol 1999;13:787-796.
31. Caldon CE. Estrogen signaling and the DNA damage response in hormone dependent breast cancers. Front Oncol 2014;4:106.
32. De Pergola G, Silvestris F. Obesity as a major risk factor for cancer. J Obes 2013;2013:291546.
33. Gunter MJ, Hoover DR, Yu H et al. Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 2009; 101:48-60.
34. Renehan AG, Frystyk J, Flyvbjerg A. Obesity and cancer risk: The role of the insulin-IGF axis. Trends Endocrinol Metab 2006;17:328-336.
35. Calle EE, Kaaks R. Overweight, obesity and cancer: Epidemiological evidence and proposed mechanisms. Nat Rev Cancer 2004;4:579-591.
36. Frasca F, Pandini G, Sciacca L et al. The role of insulin receptors and IGF-I receptors in cancer and other diseases. Arch Physiol Biochem 2008;114: 23-37.
37. Frasca F, Pandini G, Vigneri R et al. Insulin and hybrid insulin/IGF receptors are major regulators of breast cancer cells. Breast Dis 2003;17:73-89.
38. Gallagher EJ, LeRoith D. The proliferating role of insulin and insulin-like growth factors in cancer. Trends Endocrinol Metab 2010;21:610-618.
39. Novosyadlyy R, Lann DE, Vijayakumar A et al. Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. Cancer Res 2010;70: 741-751.
40. Magnuson B, Ekim B, Fingar DC. Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem J 2012; 441:1-21.
41. Zhou X, Tan M, Stone Hawthorne V et al. Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clin Cancer Res 2004;10:6779-6788.
42. Bose S, Chandran S, Mirocha JM et al. The Akt pathway in human breast cancer: A tissue-arraybased analysis. Mod Pathol 2006;19:238-245.
43. Bostner J, Karlsson E, Pandiyan MJ et al. Activation of Akt, mTOR, and the estrogen receptor as a signature to predict tamoxifen treatment benefit. Breast Cancer Res Treat 2013;137:397-406.
44. García-Jiménez C, García-Martínez JM, Chocarro-Calvo A et al. A new link between diabetes and cancer: Enhanced WNT/b-catenin signaling by high glucose. JMol Endocrinol 2014;52:R51-R66.
45. Clevers H, Nusse R. Wnt/b-catenin signaling and disease. Cell 2012;149:1192-1205.
46. Naidu R, Yip CH, Taib NA. Genetic variations in transcription factor 7-like 2 (TCF7L2) gene: Association of TCF7L2 rs12255372(G/T) or rs7903146(C/T) with breast cancer risk and clinico-pathological parameters. Med Oncol 2012;29:411-417.
47. Vona-Davis L, Rose DP. Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr Relat Cancer 2007;14:189-206.
48. Guo S, Liu M, Wang G et al. Oncogenic role and therapeutic target of leptin signaling in breast cancer and cancer stem cells. Biochim Biophys Acta 2012;1825: 207-222.
49. Dalamaga M. Obesity, insulin resistance, adipocytokines and breast cancer: New biomarkers and attractive therapeutic targets. World J Exp Med 2013;3:34-42.
50. Yin N, Wang D, Zhang H et al. Molecular mechanisms involved in the growth stimulation of breast cancer cells by leptin. Cancer Res 2004;64: 5870-5875.
51. Catalano S, Marsico S, Giordano C et al. Leptin enhances, via AP-1, expression of aromatase in the MCF-7cell line. JBiolChem 2003;278:28668-28676.
52. Macciò A, Madeddu C, Gramignano G et al. Correlationofbodymass indexand leptin with tumor size and stage of disease in hormone-dependent postmenopausal breast cancer: Preliminary results and therapeutic implications. J MolMed (Berl) 2010; 88:677-686.
53. Brown KA, McInnes KJ, Hunger NI et al. Subcellular localization of cyclic AMP-responsive element binding protein-regulated transcription coactivator 2 provides a link between obesity and breast cancer in postmenopausal women. Cancer Res 2009;69:5392-5399.
54. Yamauchi T, Kadowaki T. Physiological and pathophysiological roles of adiponectin and adiponectin receptors in the integrated regulation of metabolic and cardiovascular diseases. Int J Obes 2008;32(suppl 7):S13-S18.
55. Iyengar NM, Hudis CA, Dannenberg AJ. Obesity and inflammation: New insights into breast cancer development and progression. Am Soc Clin Oncol Educ Book 2013;46-51.
56. Cinti S, Mitchell G, Barbatelli G et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 2005;46:2347-2355.
57. Subbaramaiah K, Howe LR, Bhardwaj P et al. Obesity is associated with inflammation and elevated aromatase expression in the mouse mammary gland. Cancer Prev Res (Phila) 2011;4:329-346.
58. Shi H, Kokoeva MV, Inouye K et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 2006;116:3015-3025.
59. Carter JC, Church FC. Obesity and breast cancer: The roles of peroxisome proliferatoractivated receptor-g and plasminogen activator inhibitor-1. PPAR Res 2009;2009:345320.
60. Seibold P, Hein R, Schmezer P et al. Polymorphisms in oxidative stress-related genes and postmenopausal breast cancer risk. Int J Cancer 2011; 129:1467-1476.
61. Newman B, Austin MA, Lee M et al. Inheritance of human breast cancer: Evidence for autosomal dominant transmission in high-risk families. Proc Natl Acad Sci USA 1988;85:3044-3048.
62. García JM, Silva J, Peña C et al. Promoter methylation of the PTEN gene is a common molecular change in breast cancer. Genes Chromosomes Cancer 2004;41:117-124.
63. Chen J, Lindblom A. Germline mutation screening of the STK11/LKB1 gene in familial breast cancer with LOH on 19p. Clin Genet 2000;57: 394-397.
64. Kuusisto KM, Bebel A, Vihinen M et al. Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals. Breast Cancer Res 2011; 13:R20.
65. Lichtenstein P, Holm NV, Verkasalo PK et al. Environmental and heritable factors in the causation of cancer—Analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl JMed 2000; 343:78-85.
66. Snoussi K, Strosberg AD, Bouaouina N et al. Leptin and leptin receptor polymorphisms are associated with increased risk and poor prognosis of breast carcinoma. BMC Cancer 2006;6:38.
67. Gallicchio L, McSorley MA, Newschaffer CJ et al. Body mass, polymorphisms in obesity-related genes, and the risk of developing breast cancer among women with benign breast disease. Cancer Detect Prev 2007;31:95-101.
68. Liu C, Liu L. Polymorphisms in three obesityrelated genes (LEP, LEPR, and PON1) and breast cancer risk: A meta-analysis. Tumour Biol 2011;32: 1233-1240.
69. Cleveland RJ, Gammon MD, Long CM et al. Common genetic variations in the LEP and LEPR genes, obesity and breast cancer incidence and survival. Breast Cancer Res Treat 2010;120:745-752.
70. Terrasi M, Fiorio E, Mercanti A et al. Functional analysis of the-2548G/A leptin gene polymorphism in breast cancer cells. Int J Cancer 2009;125: 1038-1044.
71. Pande M, Bondy ML, Do KA et al. Association betweengermline single nucleotide polymorphisms in the PI3K-AKT-mTOR pathway, obesity, and breast cancer disease-free survival. BreastCancer ResTreat 2014;147:381-387.
72. Ferretti G, Bacchetti T, Moroni C et al. Paraoxonase activity in high-density lipoproteins: A comparison between healthy and obese females. J Clin Endocrinol Metab 2005;90:1728-1733.
73. Gómez Flores-Ramos L, Escoto-De Dios A, Puebla-Pérez AM et al. Association of the tumor necrosis factor-alpha 2308G. A polymorphism with breast cancer in Mexican women. Genet Mol Res 2013;12:5680-5693.
74. Alokail MS, Al-Daghri NM, Al-Attas OS et al. Combined effects of obesity and type 2 diabetes contribute to increased breast cancer risk in premenopausalwomen. Cardiovasc Diabetol 2009;8:33.
75. Frayling TM, Timpson NJ, Weedon MN et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007;316:889-894.
76. Kusinska R, Górniak P, Pastorczak A et al. Influence of genomic variation in FTO at 16q12. 2, MC4Rat18q22andNRXN3at14q31genesonbreast cancer risk. Mol Biol Rep 2012;39:2915-2919.
77. da Cunha PA, de Carlos Back LK, Sereia AF et al. Interaction between obesity-related genes, FTOand MC4R, associated to an increase of breast cancer risk. Mol Biol Rep 2013;40:6657-6664.
78. Kaklamani V, Yi N, Sadim M et al. The role of the fat mass and obesity associated gene (FTO) in breast cancer risk. BMC Med Genet 2011;12:52.
79. Miyoshi Y, Funahashi T, Kihara S et al. Association of serum adiponectin levels with breast cancer risk. Clin Cancer Res 2003;9:5699-5704.
80. Kaklamani VG, Hoffmann TJ, Thornton TA et al. Adiponectin pathway polymorphisms and risk of breast cancer in African Americans and Hispanics in the Women’s Health Initiative. Breast Cancer Res Treat 2013;139:461-468.
81. Al Khaldi RM, Al Mulla F, Al Awadhi S et al. Associations of single nucleotide polymorphisms in the adiponectin gene with adiponectin levels and cardio-metabolic risk factors in patients with cancer. Dis Markers 2011;30:197-212.
82. Mohan Reddy N, Kalyana Kumar CH, Kaiser J. Association of adiponectin gene functional polymorphisms (145T/G and 276G/T) with obese breast cancer. J Mol Biomark Diagn 2012;3:6.
83. Kaklamani VG, Sadim M, Hsi A et al. Variants of the adiponectin and adiponectin receptor 1 genes and breast cancer risk. Cancer Res 2008;68:3178-3184.
84. Connor A, Baumgartner RN, Kerber RA et al. ADRB2 G-G haplotype associatedwith breast cancer riskamong Hispanic and non-Hispanic white women: Interaction with type 2 diabetes and obesity. Cancer Causes Control 2012;23:1653-1663.
85. Ng ST, Zhou J, Adesanya OO et al. Growth hormone treatment induces mammary gland hyperplasia in aging primates. Nat Med 1997;3: 1141-1144.
86. Faber P, Johnstone AM, Gibney ER et al. The effect of rate of weight loss on erythrocyte glutathione concentration and synthesis in healthy obese men. Clin Sci (Lond) 2002;102:569-577.
87. Helzlsouer KJ, Selmin O, Huang HY et al. Association between glutathione S-transferase M1, P1, and T1 genetic polymorphisms and development of breast cancer. J Natl Cancer Inst 1998;90: 512-518.
88. Yu H, Li BD, Smith M et al. Polymorphic CA repeats in the IGF-I gene and breast cancer. Breast Cancer Res Treat 2001;70:117-122.
89. Missmer SA, Haiman CA, Hunter DJ et al. A sequence repeat in the insulin-like growth factor-1 gene and risk of breast cancer. Int JCancer 2002;100: 332-336.
90. DeLellis K, Ingles S, Kolonel L et al. IGF1 genotype, mean plasma level and breast cancer risk in the Hawaii/Los Angeles multiethnic cohort. Br J Cancer 2003;88:277-282.
91. Wen W, Gao YT, Shu X O et al. Insulin-likegrowth factor-Igene polymorphism andbreast cancer risk in Chinese women. Int J Cancer 2005;113:307-311.
92. Pang B, Cheng S, Sun SP et al. Prognostic role of PIK3CAmutations and their associationwith hormone receptor expression in breast cancer: Ameta-analysis. Sci Rep 2014;4:6255.
93. Wasserman L, Flatt SW, Natarajan L et al. Correlates of obesity in postmenopausal women with breast cancer: Comparison of genetic, demographic, disease-related, lifehistoryanddietary factors. Int J Obes RelatMetab Disord 2004;28:49-56.
94. De Vivo I, Hankinson SE, Colditz GA et al. A functional polymorphism in the progesterone receptor gene is associated with an increase in breast cancer risk. Cancer Res 2003;63:5236-5238.
95. Miyoshi Y, Funahashi T, Tanaka S et al. High expression of leptin receptormRNAin breast cancer tissue predictspoorprognosis for patients with high, but not low, serum leptin levels. Int J Cancer 2006; 118:1414-1419.
96. Tessitore L, Vizio B, Pesola D et al. Adipocyte expression and circulating levels of leptin increase in both gynaecological and breast cancer patients. Int J Oncol 2004;24:1529-1535.
97. Machinal-Quélin F, Dieudonné MN, Pecquery R et al. Direct in vitro effects of androgens and estrogens on ob gene expression and leptin secretion in human adipose tissue. Endocrine 2002;18:179-184.
98. Geisler J, Haynes B, Ekse D et al. Total body aromatization in postmenopausal breast cancer patients is strongly correlated to plasma leptin levels. J Steroid Biochem Mol Biol 2007;104:27-34.
99. Mantzoros C, Petridou E, Dessypris N et al. Adiponectin and breast cancer risk. J Clin Endocrinol Metab 2004;89:1102-1107.
100. Tworoger SS, Eliassen AH, Kelesidis T et al. Plasma adiponectin concentrations and risk of incident breast cancer. J Clin Endocrinol Metab 2007;92:1510-1516.
101. Fasshauer M, Klein J, Neumann S et al. Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2002;290:1084-1089.
102. Sheen-Chen SM, Liu YW, Eng HL et al. Serum levels of hepatocyte growth factor in patients with breast cancer. Cancer Epidemiol Biomarkers Prev 2005;14:715-717.
103. Sundaram S, Freemerman AJ, Johnson AR et al. Role of HGF in obesity-associated tumorigenesis: C3(1)-TAgmice as amodel for human basal-like breast cancer. Breast Cancer Res Treat 2013;142: 489-503.
104. Gunter MJ, Hoover DR, Yu H et al. Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 2009; 101:48-60.
105. Alluri PG, Speers C, Chinnaiyan AM. Estrogen receptor mutations and their role in breast cancer progression. Breast Cancer Res 2014;16:494.
106. Fuentes-Mattei E, Velazquez-Torres G, Phan L et al. Effects of obesity on transcriptomic changes and cancer hallmarks in estrogen receptor-positive breast cancer. J Natl Cancer Inst 2014;106:dju158.
107. Creighton CJ, Sada YH, Zhang Y et al. A gene transcription signature of obesity in breast cancer. Breast Cancer Res Treat 2012;132:993-1000.
108. Creighton CJ, Casa A, LazardZet al. Insulin-like growth factor-I activates gene transcription programs strongly associated with poor breast cancer prognosis. J Clin Oncol 2008;26:4078-4085.
109. Dalmau E, Armengol-Alonso A, Muñoz M et al. Current status of hormone therapy in patients with hormone receptor positive (HR1) advanced breast cancer. Breast 2014;23:710-720.
110. Goodwin PJ. Obesity and endocrine therapy: Host factors and breast cancer outcome. Breast 2013;22(suppl 2):S44-S47.
111. Howell A, Cuzick J, Baum M et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005; 365:60-62.
112. Gnant M, Mlineritsch B, Stoeger H et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol 2011;12:631-641.
113. Garreau JR, Delamelena T, Walts D et al. Side effects of aromatase inhibitors versus tamoxifen: The patients’ perspective. Am J Surg 2006;192: 496-498.
114. Baselga J, Campone M, Piccart M et al. Everolimus in postmenopausal hormone-receptorpositive advanced breast cancer. N Engl JMed 2012; 366:520-529.
115. Bachelot T, Bourgier C, Cropet C et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: A GINECO study. J Clin Oncol 2012;30:2718-2724.
116. Ma CX, Suman VJ, Goetz M et al. Aphase I trial of the IGF-1R antibody cixutumumab in combination with temsirolimus in patients with metastatic breast cancer. Breast Cancer Res Treat 2013;139: 145-153.
117. Lee DF, Kuo HP, Chen CT et al. IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 2007;130: 440-455.
118. Chen CT, Du Y, Yamaguchi H et al. Targetingthe IKKb/mTOR/VEGF signaling pathway as a potential therapeutic strategy for obesity-related breast cancer. Mol Cancer Ther 2012;11:2212-2221.
119. De Angel RE, Conti CJ, Wheatley KE et al. The enhancing effects of obesity on mammary tumor growth and Akt/mTOR pathway activation persist after weight loss and are reversed by RAD001. Mol Carcinog 2013;52:446-458.
120. Um SH, Frigerio F, Watanabe M et al. Absence of S6K1 protects against age-and diet-induced obesity while enhancing insulin sensitivity. Nature 2004;431:200-205.
121. Sivendran S, Agarwal N, Gartrell B et al. Metabolic complications with the use of mTOR inhibitors for cancer therapy. Cancer TreatRev 2014; 40:190-196.
122. Fraenkel M, Ketzinel-Gilad M, Ariav Y et al. mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 2008; 57:945-957.
123. Zhou G, Myers R, Li Y et al. Role of AMPactivated protein kinase inmechanismof metformin action. J Clin Invest 2001;108:1167-1174.
124. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003;115:577-590.
125. Alimova IN, Liu B, Fan Z et al. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle 2009; 8:909-915.
126. Hirsch HA, Iliopoulos D, Tsichlis PN et al. Metformin selectively targets cancer stemcells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 2009;69: 7507-7511.
127. Phoenix KN, Vumbaca F, Claffey KP. Therapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ERalpha negative MDA-MB-435 breast cancer model. Breast Cancer Res Treat 2009;113:101-111.
128. Sivalingam VN, Myers J, Nicholas S et al. Metformin in reproductive health, pregnancy and gynaecological cancer: Established and emerging indications. Hum Reprod Update 2014;20:853-868.
129. Jiralerspong S, Palla SL, Giordano SH et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 2009;27: 3297-3302.