Obesity, Inflammation, and Breast Cancer

  • Neil M. Iyengar
  • Patrick G. Morris
  • Clifford A. Hudis
  • Andrew J. DannenbergEmail author
Part of the Energy Balance and Cancer book series (EBAC, volume 7)


Obesity, which is rising in incidence worldwide, is important with regard to the treatment of breast cancer, disease progression, and carcinogenesis. Obesity is a risk factor for the development of hormone receptor-positive breast cancer in postmenopausal women and is associated with reduced benefits from treatment. Furthermore, irrespective of breast cancer subtype, obesity is associated with worse outcomes after diagnosis. There is increasing evidence of specific biological underpinnings for these observations, including higher circulating estrogen levels, insulin resistance, altered levels of adipokines, and the consequences of chronic in-breast inflammation. Increasing adiposity also has important implications for local therapy including surgery and radiotherapy. This chapter reviews the complex interactions between obesity and breast cancer.


Breast Cancer Body Mass Index Obese Patient Obese Woman Breast Cancer Diagnosis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



5′-Adenosine monophosphate-activated protein kinase


Breast cancer-specific survival


Body mass index


CCAAT/enhancer binding protein-α


Confidence interval


Crown-like structures


Disease-free survival


Estrogen receptor


Free fatty acid


Human epidermal growth factor receptor-2


Hazard ratio


High-sensitivity C-reactive protein


Insulin-like growth factor-1








Nonsteroidal anti-inflammatory drug


Odds ratio


Overall survival


Prostaglandin E2


Peroxisome proliferator-activated receptor-γ


Progesterone receptor


Relative risk


Selective estrogen receptor modulator


Sex hormone-binding globulin


Toll-like receptor-2


Toll-like receptor-4


Tumor necrosis factor-α


Transverse rectus abdominis myocutaneous



This work was supported by NCI 1R01CA154481, the Breast Cancer Research Foundation, and the Botwinick-Wolfensohn Foundation (in memory of Mr. and Mrs. Benjamin Botwinick).


  1. 1.
    Wang YC, McPherson K, Marsh T, Gortmaker SL, Brown M (2011) Health and economic burden of the projected obesity trends in the USA and the UK. Lancet 378(9793):815–825. doi:S0140-6736(11)60814-3 [pii] 10.1016/S0140-6736(11)60814-3 [doi]PubMedCrossRefGoogle Scholar
  2. 2.
    Centers for disease control and prevention: overweight and obesity. http://wwwcdcgov/­obesity/indexhtml
  3. 3.
    Levi J, Segal LM, St. Laurent R, Lang A, Rayburn J (2012) F as in fat: how obesity threatens America’s future 2012. Trust for America’s Health. Accessed 28 Sept 2012.
  4. 4.
    Cleary MP, Grossmann ME (2009) Minireview: obesity and breast cancer: the estrogen connection. Endocrinology 150(6):2537–2542. doi: 10.1210/en.2009-0070 PubMedCrossRefGoogle Scholar
  5. 5.
    van Kruijsdijk RC, van der Wall E, Visseren FL (2009) Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev 18(10):2569–2578. doi: 10.1158/1055-9965.EPI-09-0372 PubMedCrossRefGoogle Scholar
  6. 6.
    van den Brandt PA, Spiegelman D, Yaun SS, Adami HO, Beeson L, Folsom AR, Fraser G, Goldbohm RA, Graham S, Kushi L, Marshall JR, Miller AB, Rohan T, Smith-Warner SA, Speizer FE, Willett WC, Wolk A, Hunter DJ (2000) Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk. Am J Epidemiol 152(6):514–527PubMedCrossRefGoogle Scholar
  7. 7.
    Trentham-Dietz A, Newcomb PA, Storer BE, Longnecker MP, Baron J, Greenberg ER, Willett WC (1997) Body size and risk of breast cancer. Am J Epidemiol 145(11):1011–1019PubMedCrossRefGoogle Scholar
  8. 8.
    Key TJ, Appleby PN, Reeves GK, Roddam A, Dorgan JF, Longcope C, Stanczyk FZ, Stephenson HE Jr, Falk RT, Miller R, Schatzkin A, Allen DS, Fentiman IS, Wang DY, Dowsett M, Thomas HV, Hankinson SE, Toniolo P, Akhmedkhanov A, Koenig K, Shore RE, Zeleniuch-Jacquotte A, Berrino F, Muti P, Micheli A, Krogh V, Sieri S, Pala V, Venturelli E, Secreto G, Barrett-Connor E, Laughlin GA, Kabuto M, Akiba S, Stevens RG, Neriishi K, Land CE, Cauley JA, Kuller LH, Cummings SR, Helzlsouer KJ, Alberg AJ, Bush TL, Comstock GW, Gordon GB, Miller SR (2003) Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 95(16):1218–1226PubMedCrossRefGoogle Scholar
  9. 9.
    Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348(17):1625–1638. doi: 10.1056/NEJMoa021423 PubMedCrossRefGoogle Scholar
  10. 10.
    La Vecchia C, Negri E, Franceschi S, Talamini R, Bruzzi P, Palli D, Decarli A (1997) Body mass index and post-menopausal breast cancer: an age-specific analysis. Br J Cancer 75(3):441–444PubMedCrossRefGoogle Scholar
  11. 11.
    Lorincz AM, Sukumar S (2006) Molecular links between obesity and breast cancer. Endocr Relat Cancer 13(2):279–292. doi: 10.1677/erc.1.00729 PubMedCrossRefGoogle Scholar
  12. 12.
    Li CI, Daling JR, Malone KE (2003) Incidence of invasive breast cancer by hormone receptor status from 1992 to 1998. J Clin Oncol 21(1):28–34PubMedCrossRefGoogle Scholar
  13. 13.
    Wake DJ, Strand M, Rask E, Westerbacka J, Livingstone DE, Soderberg S, Andrew R, Yki-­Jarvinen H, Olsson T, Walker BR (2007) Intra-adipose sex steroid metabolism and body fat distribution in idiopathic human obesity. Clin Endocrinol 66(3):440–446. doi: 10.1111/j.1365-2265.2007.02755.x CrossRefGoogle Scholar
  14. 14.
    Daling JR, Malone KE, Doody DR, Johnson LG, Gralow JR, Porter PL (2001) Relation of body mass index to tumor markers and survival among young women with invasive ductal breast carcinoma. Cancer 92(4):720–729PubMedCrossRefGoogle Scholar
  15. 15.
    Fagherazzi G, Chabbert-Buffet N, Fabre A, Guillas G, Boutron-Ruault MC, Mesrine S, Clavel-Chapelon F (2012) Hip circumference is associated with the risk of premenopausal ER-/PR- breast cancer. Int J Obes (Lond) 36(3):431–439. doi: 10.1038/ijo.2011.66 CrossRefGoogle Scholar
  16. 16.
    Pierce BL, Ballard-Barbash R, Bernstein L, Baumgartner RN, Neuhouser ML, Wener MH, Baumgartner KB, Gilliland FD, Sorensen BE, McTiernan A, Ulrich CM (2009) Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients. J Clin Oncol 27(21):3437–3444. doi: 10.1200/JCO.2008.18.9068 PubMedCrossRefGoogle Scholar
  17. 17.
    Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219–246. doi: 10.1146/annurev-physiol-021909-135846 PubMedCrossRefGoogle Scholar
  18. 18.
    Tilg H, Moschen AR (2006) Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6(10):772–783. doi: 10.1038/nri1937 PubMedCrossRefGoogle Scholar
  19. 19.
    Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112(12):1821–1830. doi: 10.1172/JCI19451 PubMedGoogle Scholar
  20. 20.
    Skurk T, Alberti-Huber C, Herder C, Hauner H (2007) Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab 92(3):1023–1033. doi: 10.1210/jc.2006-1055 PubMedCrossRefGoogle Scholar
  21. 21.
    Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA (2001) Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86(5):1930–1935PubMedCrossRefGoogle Scholar
  22. 22.
    Mantzoros C, Petridou E, Dessypris N, Chavelas C, Dalamaga M, Alexe DM, Papadiamantis Y, Markopoulos C, Spanos E, Chrousos G, Trichopoulos D (2004) Adiponectin and breast cancer risk. J Clin Endocrinol Metab 89(3):1102–1107PubMedCrossRefGoogle Scholar
  23. 23.
    Grossmann ME, Nkhata KJ, Mizuno NK, Ray A, Cleary MP (2008) Effects of adiponectin on breast cancer cell growth and signaling. Br J Cancer 98(2):370–379. doi: 10.1038/sj.bjc.6604166 PubMedCrossRefGoogle Scholar
  24. 24.
    Jarde T, Perrier S, Vasson MP, Caldefie-Chezet F (2011) Molecular mechanisms of leptin and adiponectin in breast cancer. Eur J Cancer 47(1):33–43. doi: 10.1016/j.ejca.2010.09.005 PubMedCrossRefGoogle Scholar
  25. 25.
    Jarde T, Caldefie-Chezet F, Damez M, Mishellany F, Penault-Llorca F, Guillot J, Vasson MP (2008) Leptin and leptin receptor involvement in cancer development: a study on human primary breast carcinoma. Oncol Rep 19(4):905–911PubMedGoogle Scholar
  26. 26.
    Revillion F, Charlier M, Lhotellier V, Hornez L, Giard S, Baranzelli MC, Djiane J, Peyrat JP (2006) Messenger RNA expression of leptin and leptin receptors and their prognostic value in 322 human primary breast cancers. Clin Cancer Res 12(7 pt 1):2088–2094. doi: 10.1158/1078-0432.CCR-05-1904 PubMedCrossRefGoogle Scholar
  27. 27.
    Okumura M, Yamamoto M, Sakuma H, Kojima T, Maruyama T, Jamali M, Cooper DR, Yasuda K (2002) Leptin and high glucose stimulate cell proliferation in MCF-7 human breast cancer cells: reciprocal involvement of PKC-alpha and PPAR expression. Biochim Biophys Acta 1592(2):107–116PubMedGoogle Scholar
  28. 28.
    Caldefie-Chezet F, Damez M, de Latour M, Konska G, Mishellani F, Fusillier C, Guerry M, Penault-Llorca F, Guillot J, Vasson MP (2005) Leptin: a proliferative factor for breast cancer? Study on human ductal carcinoma. Biochem Biophys Res Commun 334(3):737–741. doi: 10.1016/j.bbrc.2005.06.077 PubMedCrossRefGoogle Scholar
  29. 29.
    Garofalo C, Koda M, Cascio S, Sulkowska M, Kanczuga-Koda L, Golaszewska J, Russo A, Sulkowski S, Surmacz E (2006) Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: possible role of obesity-related stimuli. Clin Cancer Res 12(5):1447–1453. doi: 10.1158/1078-0432.CCR-05-1913 PubMedCrossRefGoogle Scholar
  30. 30.
    Ishikawa M, Kitayama J, Nagawa H (2004) Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res 10(13):4325–4331. doi: 10.1158/1078-­0432.CCR-03-0749 PubMedCrossRefGoogle Scholar
  31. 31.
    Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Madarnas Y, Hartwick W, Hoffman B, Hood N (2002) Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol 20(1):42–51PubMedCrossRefGoogle Scholar
  32. 32.
    Pollak MN, Schernhammer ES, Hankinson SE (2004) Insulin-like growth factors and neoplasia. Nat Rev Cancer 4(7):505–518. doi: 10.1038/nrc1387 PubMedCrossRefGoogle Scholar
  33. 33.
    Chong YM, Colston K, Jiang WG, Sharma AK, Mokbel K (2006) The relationship between the insulin-like growth factor-1 system and the oestrogen metabolising enzymes in breast cancer tissue and its adjacent non-cancerous tissue. Breast Cancer Res Treat 99(3):275–288. doi: 10.1007/s10549-006-9215-y PubMedCrossRefGoogle Scholar
  34. 34.
    Lueprasitsakul P, Latour D, Longcope C (1990) Aromatase activity in human adipose tissue stromal cells: effect of growth factors. Steroids 55(12):540–544PubMedCrossRefGoogle Scholar
  35. 35.
    Baglietto L, English DR, Hopper JL, MacInnis RJ, Morris HA, Tilley WD, Krishnan K, Giles GG (2009) Circulating steroid hormone concentrations in postmenopausal women in relation to body size and composition. Breast Cancer Res Treat 115(1):171–179. doi: 10.1007/s10549-008-0069-3 PubMedCrossRefGoogle Scholar
  36. 36.
    Morris PG, Hudis CA, Giri D, Morrow M, Falcone DJ, Zhou XK, Du B, Brogi E, Crawford CB, Kopelovich L, Subbaramaiah K, Dannenberg AJ (2011) Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer. Cancer Prev Res (Phila) 4(7):1021–1029. doi: 10.1158/1940-6207.CAPR-11-0110 CrossRefGoogle Scholar
  37. 37.
    Cancello R, Henegar C, Viguerie N, Taleb S, Poitou C, Rouault C, Coupaye M, Pelloux V, Hugol D, Bouillot JL, Bouloumie A, Barbatelli G, Cinti S, Svensson PA, Barsh GS, Zucker JD, Basdevant A, Langin D, Clement K (2005) Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 54(8):2277–2286PubMedCrossRefGoogle Scholar
  38. 38.
    Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS (2005) Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 46(11):2347–2355. doi: 10.1194/jlr.M500294-JLR200 PubMedCrossRefGoogle Scholar
  39. 39.
    Mathis D, Shoelson SE (2011) Immunometabolism: an emerging frontier. Nat Rev Immunol 11(2):81. doi: 10.1038/nri2922 PubMedCrossRefGoogle Scholar
  40. 40.
    Monteiro R, Azevedo I (2010) Chronic inflammation in obesity and the metabolic syndrome. Mediators Inflamm 2010. doi: 10.1155/2010/289645
  41. 41.
    Hotamisligil GS (2010) Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140(6):900–917. doi: 10.1016/j.cell.2010.02.034 PubMedCrossRefGoogle Scholar
  42. 42.
    Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate ­immunity and fatty acid-induced insulin resistance. J Clin Invest 116(11):3015–3025. doi: 10.1172/JCI28898 PubMedCrossRefGoogle Scholar
  43. 43.
    Bachelot T, Ray-Coquard I, Menetrier-Caux C, Rastkha M, Duc A, Blay JY (2003) Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients. Br J Cancer 88(11):1721–1726. doi: 10.1038/sj.bjc.6600956 PubMedCrossRefGoogle Scholar
  44. 44.
    Dandona P, Weinstock R, Thusu K, Abdel-Rahman E, Aljada A, Wadden T (1998) Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. J Clin Endocrinol Metab 83(8):2907–2910PubMedCrossRefGoogle Scholar
  45. 45.
    Vozarova B, Weyer C, Hanson K, Tataranni PA, Bogardus C, Pratley RE (2001) Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes Res 9(7):414–417. doi: 10.1038/oby.2001.54 PubMedCrossRefGoogle Scholar
  46. 46.
    Nguyen MT, Favelyukis S, Nguyen AK, Reichart D, Scott PA, Jenn A, Liu-Bryan R, Glass CK, Neels JG, Olefsky JM (2007) A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-­dependent pathways. J Biol Chem 282(48):35279–35292. doi: 10.1074/jbc.M706762200 PubMedCrossRefGoogle Scholar
  47. 47.
    Murano I, Barbatelli G, Parisani V, Latini C, Muzzonigro G, Castellucci M, Cinti S (2008) Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J Lipid Res 49(7):1562–1568. doi: 10.1194/jlr.M800019-JLR200 PubMedCrossRefGoogle Scholar
  48. 48.
    Subbaramaiah K, Howe LR, Bhardwaj P, Du B, Gravaghi C, Yantiss RK, Zhou XK, Blaho VA, Hla T, Yang P, Kopelovich L, Hudis CA, Dannenberg AJ (2011) Obesity is associated with inflammation and elevated aromatase expression in the mouse mammary gland. Cancer Prev Res (Phila) 4(3):329–346. doi: 10.1158/1940-6207.CAPR-10-0381 CrossRefGoogle Scholar
  49. 49.
    Sun X, Casbas-Hernandez P, Bigelow C, Makowski L, Joseph Jerry D, Smith Schneider S, Troester MA (2012) Normal breast tissue of obese women is enriched for macrophage markers and macrophage-associated gene expression. Breast Cancer Res Treat 131(3):1003–1012. doi: 10.1007/s10549-011-1789-3 PubMedCrossRefGoogle Scholar
  50. 50.
    Subbaramaiah K, Morris PG, Zhou XK, Morrow M, Du B, Giri D, Kopelovich L, Hudis CA, Dannenberg AJ (2012) Increased levels of COX-2 and prostaglandin E2 contribute to elevated aromatase expression in inflamed breast tissue of obese women. Cancer Discov 2(4):356–365. doi: 10.1158/2159-8290.CD-11-0241 PubMedCrossRefGoogle Scholar
  51. 51.
    McTiernan A, Rajan KB, Tworoger SS, Irwin M, Bernstein L, Baumgartner R, Gilliland F, Stanczyk FZ, Yasui Y, Ballard-Barbash R (2003) Adiposity and sex hormones in postmenopausal breast cancer survivors. J Clin Oncol 21(10):1961–1966. doi: 10.1200/JCO.2003.07.057 PubMedCrossRefGoogle Scholar
  52. 52.
    Bulun SE, Lin Z, Imir G, Amin S, Demura M, Yilmaz B, Martin R, Utsunomiya H, Thung S, Gurates B, Tamura M, Langoi D, Deb S (2005) Regulation of aromatase expression in estrogen-­responsive breast and uterine disease: from bench to treatment. Pharmacol Rev 57(3):359–383. doi: 10.1124/pr.57.3.6 PubMedCrossRefGoogle Scholar
  53. 53.
    Irahara N, Miyoshi Y, Taguchi T, Tamaki Y, Noguchi S (2006) Quantitative analysis of aromatase mRNA expression derived from various promoters (I.4, I.3, PII and I.7) and its association with expression of TNF-alpha, IL-6 and COX-2 mRNAs in human breast cancer. Int J Cancer 118(8):1915–1921. doi: 10.1002/ijc.21562 PubMedCrossRefGoogle Scholar
  54. 54.
    Zhao Y, Agarwal VR, Mendelson CR, Simpson ER (1996) Estrogen biosynthesis proximal to a breast tumor is stimulated by PGE2 via cyclic AMP, leading to activation of promoter II of the CYP19 (aromatase) gene. Endocrinology 137(12):5739–5742PubMedCrossRefGoogle Scholar
  55. 55.
    Daniell HW (1988) Increased lymph node metastases at mastectomy for breast cancer associated with host obesity, cigarette smoking, age, and large tumor size. Cancer 62(2):429–435PubMedCrossRefGoogle Scholar
  56. 56.
    Sohrabi A, Sandoz J, Spratt JS, Polk HC Jr (1980) Recurrence of breast cancer. Obesity, tumor size, and axillary lymph node metastases. JAMA 244(3):264–265PubMedCrossRefGoogle Scholar
  57. 57.
    Boyd NF, Campbell JE, Germanson T, Thomson DB, Sutherland DJ, Meakin JW (1981) Body weight and prognosis in breast cancer. J Natl Cancer Inst 67(4):785–789PubMedGoogle Scholar
  58. 58.
    Cui Y, Whiteman MK, Flaws JA, Langenberg P, Tkaczuk KH, Bush TL (2002) Body mass and stage of breast cancer at diagnosis. Int J Cancer 98(2):279–283PubMedCrossRefGoogle Scholar
  59. 59.
    Hunt KA, Sickles EA (2000) Effect of obesity on screening mammography: outcomes ­analysis of 88,346 consecutive examinations. AJR Am J Roentgenol 174(5):1251–1255PubMedCrossRefGoogle Scholar
  60. 60.
    Nelson HD, Tyne K, Naik A, Bougatsos C, Chan BK, Humphrey L (2009) Screening for breast cancer: an update for the U.S. Preventive Services Task Force. Ann Inter Med 151(10):727–737, W237–W742. doi: 10.1059/0003-4819-151-10-200911170-00009 Google Scholar
  61. 61.
    Nystrom L, Andersson I, Bjurstam N, Frisell J, Nordenskjold B, Rutqvist LE (2002) Long-­term effects of mammography screening: updated overview of the Swedish randomised trials. Lancet 359(9310):909–919. doi: 10.1016/S0140-6736(02)08020-0 PubMedCrossRefGoogle Scholar
  62. 62.
    Elmore JG, Carney PA, Abraham LA, Barlow WE, Egger JR, Fosse JS, Cutter GR, Hendrick RE, D’Orsi CJ, Paliwal P, Taplin SH (2004) The association between obesity and screening mammography accuracy. Arch Intern Med 164(10):1140–1147. doi: 10.1001/archinte.164.10.1140 PubMedCrossRefGoogle Scholar
  63. 63.
    Whiteman MK, Hillis SD, Curtis KM, McDonald JA, Wingo PA, Marchbanks PA (2005) Body mass and mortality after breast cancer diagnosis. Cancer Epidemiol Biomarkers Prev 14(8):2009–2014. doi: 10.1158/1055-9965.EPI-05-0106 PubMedCrossRefGoogle Scholar
  64. 64.
    Sinicrope FA, Dannenberg AJ (2011) Obesity and breast cancer prognosis: weight of the evidence. J Clin Oncol 29(1):4–7. doi: 10.1200/JCO.2010.32.1752 PubMedCrossRefGoogle Scholar
  65. 65.
    Majed B, Moreau T, Senouci K, Salmon RJ, Fourquet A, Asselain B (2008) Is obesity an independent prognosis factor in woman breast cancer? Breast Cancer Res Treat 111(2):329–342. doi: 10.1007/s10549-007-9785-3 PubMedCrossRefGoogle Scholar
  66. 66.
    Rose DP, Vona-Davis L (2009) Influence of obesity on breast cancer receptor status and prognosis. Expert Rev Anticancer Ther 9(8):1091–1101. doi: 10.1586/era.09.71 PubMedCrossRefGoogle Scholar
  67. 67.
    Protani M, Coory M, Martin JH (2010) Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis. Breast Cancer Res Treat 123(3):627–635PubMedCrossRefGoogle Scholar
  68. 68.
    Ewertz M, Jensen MB, Gunnarsdottir KA, Hojris I, Jakobsen EH, Nielsen D, Stenbygaard LE, Tange UB, Cold S (2011) Effect of obesity on prognosis after early-stage breast cancer. J Clin Oncol 29(1):25–31. doi: 10.1200/JCO.2010.29.7614 PubMedCrossRefGoogle Scholar
  69. 69.
    Berclaz G, Li S, Price KN, Coates AS, Castiglione-Gertsch M, Rudenstam CM, Holmberg SB, Lindtner J, Erien D, Collins J, Snyder R, Thurlimann B, Fey MF, Mendiola C, Werner ID, Simoncini E, Crivellari D, Gelber RD, Goldhirsch A (2004) Body mass index as a prognostic feature in operable breast cancer: the International Breast Cancer Study Group experience. Ann Oncol 15(6):875–884PubMedCrossRefGoogle Scholar
  70. 70.
    Chen X, Lu W, Zheng W, Gu K, Chen Z, Zheng Y, Shu XO (2010) Obesity and weight change in relation to breast cancer survival. Breast Cancer Res Treat 122(3):823–833. doi: 10.1007/s10549-009-0708-3 PubMedCrossRefGoogle Scholar
  71. 71.
    Camoriano JK, Loprinzi CL, Ingle JN, Therneau TM, Krook JE, Veeder MH (1990) Weight change in women treated with adjuvant therapy or observed following mastectomy for node-­positive breast cancer. J Clin Oncol 8(8):1327–1334PubMedGoogle Scholar
  72. 72.
    Kroenke CH, Chen WY, Rosner B, Holmes MD (2005) Weight, weight gain, and survival after breast cancer diagnosis. J Clin Oncol 23(7):1370–1378. doi: 10.1200/JCO.2005.01.079 PubMedCrossRefGoogle Scholar
  73. 73.
    Levine EG, Raczynski JM, Carpenter JT (1991) Weight gain with breast cancer adjuvant treatment. Cancer 67(7):1954–1959PubMedCrossRefGoogle Scholar
  74. 74.
    Caan BJ, Kwan ML, Hartzell G, Castillo A, Slattery ML, Sternfeld B, Weltzien E (2008) Pre-­diagnosis body mass index, post-diagnosis weight change, and prognosis among women with early stage breast cancer. Cancer Causes Control 19(10):1319–1328. doi: 10.1007/s10552-008-9203-0 PubMedCrossRefGoogle Scholar
  75. 75.
    Tartter PI, Beck G, Fuchs K (1994) Determinants of hospital stay after modified radical mastectomy. Am J Surg 168(4):320–324PubMedCrossRefGoogle Scholar
  76. 76.
    El-Tamer MB, Ward BM, Schifftner T, Neumayer L, Khuri S, Henderson W (2007) Morbidity and mortality following breast cancer surgery in women: national benchmarks for standards of care. Ann Surg 245(5):665–671. doi: 10.1097/01.sla.0000245833.48399.9a PubMedCrossRefGoogle Scholar
  77. 77.
    Helyer LK, Varnic M, Le LW, Leong W, McCready D (2010) Obesity is a risk factor for developing postoperative lymphedema in breast cancer patients. Breast J 16(1):48–54. doi: 10.1111/j.1524-4741.2009.00855.x PubMedCrossRefGoogle Scholar
  78. 78.
    Mehrara BJ, Santoro TD, Arcilla E, Watson JP, Shaw WW, Da Lio AL (2006) Complications after microvascular breast reconstruction: experience with 1195 flaps. Plast Reconstr Surg 118(5):1100–1109; discussion 1110–1101. doi: 10.1097/01.prs.0000236898.87398.d6 Google Scholar
  79. 79.
    Spear SL, Ducic I, Cuoco F, Taylor N (2007) Effect of obesity on flap and donor-site complications in pedicled TRAM flap breast reconstruction. Plast Reconstr Surg 119(3):788–795. doi: 10.1097/01.prs.0000252003.14537.d2 PubMedCrossRefGoogle Scholar
  80. 80.
    McCarthy CM, Mehrara BJ, Riedel E, Davidge K, Hinson A, Disa JJ, Cordeiro PG, Pusic AL (2008) Predicting complications following expander/implant breast reconstruction: an outcomes analysis based on preoperative clinical risk. Plast Reconstr Surg 121(6):1886–1892. doi: 10.1097/PRS.0b013e31817151c4 PubMedCrossRefGoogle Scholar
  81. 81.
    Kroll SS, Netscher DT (1989) Complications of TRAM flap breast reconstruction in obese patients. Plast Reconstr Surg 84(6):886–892PubMedCrossRefGoogle Scholar
  82. 82.
    Greco JA III, Castaldo ET, Nanney LB, Wu YC, Donahue R, Wendel JJ, Hagan KF, Shack RB (2008) Autologous breast reconstruction: the Vanderbilt experience (1998 to 2005) of independent predictors of displeasing outcomes. J Am Coll Surg 207(1):49–56. doi: 10.1016/j.jamcollsurg.2007.12.052 PubMedCrossRefGoogle Scholar
  83. 83.
    Atisha DM, Alderman AK, Kuhn LE, Wilkins EG (2008) The impact of obesity on patient satisfaction with breast reconstruction. Plast Reconstr Surg 121(6):1893–1899. doi: 10.1097/PRS.0b013e3181715198 PubMedCrossRefGoogle Scholar
  84. 84.
    Alderman AK, Wilkins EG, Kim HM, Lowery JC (2002) Complications in postmastectomy breast reconstruction: two-year results of the Michigan Breast Reconstruction Outcome Study. Plast Reconstr Surg 109(7):2265–2274PubMedCrossRefGoogle Scholar
  85. 85.
    Chang DW, Wang B, Robb GL, Reece GP, Miller MJ, Evans GR, Langstein HN, Kroll SS (2000) Effect of obesity on flap and donor-site complications in free transverse rectus abdominis myocutaneous flap breast reconstruction. Plast Reconstr Surg 105(5):1640–1648PubMedCrossRefGoogle Scholar
  86. 86.
    Zampell JC, Aschen S, Weitman ES, Yan A, Elhadad S, De Brot M, Mehrara BJ (2012) Regulation of adipogenesis by lymphatic fluid stasis: part I. Adipogenesis, fibrosis, and inflammation. Plast Reconstr Surg 129(4):825–834. doi: 10.1097/PRS.0b013e3182450b2d PubMedCrossRefGoogle Scholar
  87. 87.
    Aschen S, Zampell JC, Elhadad S, Weitman E, De Brot M, Mehrara BJ (2012) Regulation of adipogenesis by lymphatic fluid stasis: part II. Expression of adipose differentiation genes. Plast Reconstr Surg 129(4):838–847. doi: 10.1097/PRS.0b013e3182450b47 PubMedCrossRefGoogle Scholar
  88. 88.
    Garvey PB, Buchel EW, Pockaj BA, Gray RJ, Samson TD (2005) The deep inferior epigastric perforator flap for breast reconstruction in overweight and obese patients. Plast Reconstr Surg 115(2):447–457PubMedCrossRefGoogle Scholar
  89. 89.
    Allen AM, Prosnitz RG, Ten Haken RK, Normolle DP, Yu X, Zhou SM, Marsh R, Marks LB, Pierce LJ (2005) Body mass index predicts the incidence of radiation pneumonitis in breast cancer patients. Cancer J 11(5):390–398PubMedCrossRefGoogle Scholar
  90. 90.
    Werner RS, McCormick B, Petrek J, Cox L, Cirrincione C, Gray JR, Yahalom J (1991) Arm edema in conservatively managed breast cancer: obesity is a major predictive factor. Radiology 180(1):177–184PubMedGoogle Scholar
  91. 91.
    Murphy C, Anderson PR, Li T, Bleicher RJ, Sigurdson ER, Goldstein LJ, Swaby R, Denlinger C, Dushkin H, Nicolaou N, Freedman GM (2011) Impact of the radiation boost on outcomes after breast-conserving surgery and radiation. Int J Radiat Oncol Biol Phys 81(1):69–76. doi: 10.1016/j.ijrobp.2010.04.067 PubMedCrossRefGoogle Scholar
  92. 92.
    Dorn PL, Corbin KS, Al-Hallaq H, Hasan Y, Chmura SJ (2012) Feasibility and acute toxicity of hypofractionated radiation in large-breasted patients. Int J Radiat Oncol Biol Phys 83(1):79–83. doi: 10.1016/j.ijrobp.2011.05.074 PubMedCrossRefGoogle Scholar
  93. 93.
    Neal AJ, Torr M, Helyer S, Yarnold JR (1995) Correlation of breast dose heterogeneity with breast size using 3D CT planning and dose-volume histograms. Radiother Oncol 34(3):210–218PubMedCrossRefGoogle Scholar
  94. 94.
    Das IJ, Cheng CW, Fein DA, Fowble B (1997) Patterns of dose variability in radiation prescription of breast cancer. Radiother Oncol 44(1):83–89PubMedCrossRefGoogle Scholar
  95. 95.
    Chen Y, Rubin P, Williams J, Hernady E, Smudzin T, Okunieff P (2001) Circulating IL-6 as a predictor of radiation pneumonitis. Int J Radiat Oncol Biol Phys 49(3):641–648PubMedCrossRefGoogle Scholar
  96. 96.
    Chen Y, Williams J, Ding I, Hernady E, Liu W, Smudzin T, Finkelstein JN, Rubin P, Okunieff P (2002) Radiation pneumonitis and early circulatory cytokine markers. Semin Radiat Oncol 12(1 suppl 1):26–33PubMedCrossRefGoogle Scholar
  97. 97.
    Lyman GH, Dale DC, Crawford J (2003) Incidence and predictors of low dose-intensity in adjuvant breast cancer chemotherapy: a nationwide study of community practices. J Clin Oncol 21(24):4524–4531. doi: 10.1200/JCO.2003.05.002 PubMedCrossRefGoogle Scholar
  98. 98.
    Griggs JJ, Sorbero ME, Lyman GH (2005) Undertreatment of obese women receiving breast cancer chemotherapy. Arch Intern Med 165(11):1267–1273. doi: 10.1001/archinte.165.11.1267 PubMedCrossRefGoogle Scholar
  99. 99.
    Bastarrachea J, Hortobagyi GN, Smith TL, Kau SW, Buzdar AU (1994) Obesity as an adverse prognostic factor for patients receiving adjuvant chemotherapy for breast cancer. Ann Intern Med 120(1):18–25PubMedCrossRefGoogle Scholar
  100. 100.
    Rosner GL, Hargis JB, Hollis DR, Budman DR, Weiss RB, Henderson IC, Schilsky RL (1996) Relationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: results from cancer and leukemia group B study 8541. J Clin Oncol 14(11):3000–3008PubMedGoogle Scholar
  101. 101.
    Georgiadis MS, Steinberg SM, Hankins LA, Ihde DC, Johnson BE (1995) Obesity and therapy-­related toxicity in patients treated for small-cell lung cancer. J Natl Cancer Inst 87(5):361–366PubMedCrossRefGoogle Scholar
  102. 102.
    Gelman RS, Tormey DC, Betensky R, Mansour EG, Falkson HC, Falkson G, Creech RH, Haller DG (1987) Actual versus ideal weight in the calculation of surface area: effects on dose of 11 chemotherapy agents. Cancer Treat Rep 71(10):907–911PubMedGoogle Scholar
  103. 103.
    Smith TJ, Desch CE (1991) Neutropenia-wise and pound-foolish: safe and effective chemotherapy in massively obese patients. South Med J 84(7):883–885PubMedCrossRefGoogle Scholar
  104. 104.
    Poikonen P, Blomqvist C, Joensuu H (2001) Effect of obesity on the leukocyte nadir in women treated with adjuvant cyclophosphamide, methotrexate, and fluorouracil dosed according to body surface area. Acta Oncol 40(1):67–71PubMedCrossRefGoogle Scholar
  105. 105.
    Griggs JJ, Mangu PB, Anderson H, Balaban EP, Dignam JJ, Hryniuk WM, Morrison VA, Pini TM, Runowicz CD, Rosner GL, Shayne M, Sparreboom A, Sucheston LE, Lyman GH (2012) Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 30(13):1553–1561. doi: 10.1200/JCO.2011.39.9436 PubMedCrossRefGoogle Scholar
  106. 106.
    Litton JK, Gonzalez-Angulo AM, Warneke CL, Buzdar AU, Kau SW, Bondy M, Mahabir S, Hortobagyi GN, Brewster AM (2008) Relationship between obesity and pathologic response to neoadjuvant chemotherapy among women with operable breast cancer. J Clin Oncol 26(25):4072–4077. doi: 10.1200/JCO.2007.14.4527 PubMedCrossRefGoogle Scholar
  107. 107.
    Chen S, Chen CM, Zhou Y, Zhou RJ, Yu KD, Shao ZM (2012) Obesity or overweight is associated with worse pathological response to neoadjuvant chemotherapy among chinese women with breast cancer. PLoS One 7(7):e41380. doi: 10.1371/journal.pone.0041380 PubMedCrossRefGoogle Scholar
  108. 108.
    de Azambuja E, McCaskill-Stevens W, Francis P, Quinaux E, Crown JP, Vicente M, Giuliani R, Nordenskjold B, Gutierez J, Andersson M, Vila MM, Jakesz R, Demol J, Dewar J, Santoro A, Lluch A, Olsen S, Gelber RD, Di Leo A, Piccart-Gebhart M (2010) The effect of body mass index on overall and disease-free survival in node-positive breast cancer patients treated with docetaxel and doxorubicin-containing adjuvant chemotherapy: the experience of the BIG 02-98 trial. Breast Cancer Res Treat 119(1):145–153. doi: 10.1007/s10549-009-0512-0 PubMedCrossRefGoogle Scholar
  109. 109.
    Sestak I, Distler W, Forbes JF, Dowsett M, Howell A, Cuzick J (2010) Effect of body mass index on recurrences in tamoxifen and anastrozole treated women: an exploratory analysis from the ATAC trial. J Clin Oncol 28(21):3411–3415. doi: 10.1200/JCO.2009.27.2021 PubMedCrossRefGoogle Scholar
  110. 110.
    Dignam JJ, Wieand K, Johnson KA, Fisher B, Xu L, Mamounas EP (2003) Obesity, tamoxifen use, and outcomes in women with estrogen receptor-positive early-stage breast cancer. J Natl Cancer Inst 95(19):1467–1476PubMedCrossRefGoogle Scholar
  111. 111.
    Sparano JA, Wang M, Zhao F, Stearns V, Martino S, Ligibel JA, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Fetting J, Davidson NE (2012) Obesity at diagnosis is associated with inferior outcomes in hormone receptor-positive operable breast cancer. Cancer 118(23):5937–5946. doi: 10.1002/cncr.27527 PubMedCrossRefGoogle Scholar
  112. 112.
    Folkerd EJ, Dixon JM, Renshaw L, A’Hern RP, Dowsett M (2012) Suppression of plasma estrogen levels by letrozole and anastrozole is related to body mass index in patients with breast cancer. J Clin Oncol 30(24):2977–2980. doi: 10.1200/JCO.2012.42.0273 PubMedCrossRefGoogle Scholar
  113. 113.
    Ligibel JA, Goodwin PJ (2012) NEW and RENEW: building the case for weight loss in breast cancer. J Clin Oncol 30(19):2294–2296. doi: 10.1200/JCO.2012.42.5496 PubMedCrossRefGoogle Scholar
  114. 114.
    Demark-Wahnefried W, Morey MC, Sloane R, Snyder DC, Miller PE, Hartman TJ, Cohen HJ (2012) Reach out to enhance wellness home-based diet-exercise intervention promotes reproducible and sustainable long-term improvements in health behaviors, body weight, and physical functioning in older, overweight/obese cancer survivors. J Clin Oncol 30(19):2354–2361. doi: 10.1200/JCO.2011.40.0895 PubMedCrossRefGoogle Scholar
  115. 115.
    Campbell KL, Foster-Schubert KE, Alfano CM, Wang CC, Wang CY, Duggan CR, Mason C, Imayama I, Kong A, Xiao L, Bain CE, Blackburn GL, Stanczyk FZ, McTiernan A (2012) Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial. J Clin Oncol 30(19):2314–2326. doi: 10.1200/JCO.2011.37.9792 PubMedCrossRefGoogle Scholar
  116. 116.
    Chlebowski RT, Aiello E, McTiernan A (2002) Weight loss in breast cancer patient management. J Clin Oncol 20(4):1128–1143PubMedCrossRefGoogle Scholar
  117. 117.
    Holmes MD, Chen WY, Feskanich D, Kroenke CH, Colditz GA (2005) Physical activity and survival after breast cancer diagnosis. JAMA 293(20):2479–2486. doi: 10.1001/jama.293.20.2479 PubMedCrossRefGoogle Scholar
  118. 118.
    Holick CN, Newcomb PA, Trentham-Dietz A, Titus-Ernstoff L, Bersch AJ, Stampfer MJ, Baron JA, Egan KM, Willett WC (2008) Physical activity and survival after diagnosis of invasive breast cancer. Cancer Epidemiol Biomarkers Prev 17(2):379–386. doi: 10.1158/1055-­9965.EPI-07-0771 PubMedCrossRefGoogle Scholar
  119. 119.
    Irwin ML, Smith AW, McTiernan A, Ballard-Barbash R, Cronin K, Gilliland FD, Baumgartner RN, Baumgartner KB, Bernstein L (2008) Influence of pre- and postdiagnosis physical activity on mortality in breast cancer survivors: the health, eating, activity, and lifestyle study. J Clin Oncol 26(24):3958–3964. doi: 10.1200/JCO.2007.15.9822 PubMedCrossRefGoogle Scholar
  120. 120.
    Chen X, Lu W, Zheng W, Gu K, Matthews CE, Chen Z, Zheng Y, Shu XO (2011) Exercise after diagnosis of breast cancer in association with survival. Cancer Prev Res (Phila) 4(9):1409–1418. doi: 10.1158/1940-6207.CAPR-10-0355 CrossRefGoogle Scholar
  121. 121.
    Chlebowski RT, Blackburn GL, Thomson CA, Nixon DW, Shapiro A, Hoy MK, Goodman MT, Giuliano AE, Karanja N, McAndrew P, Hudis C, Butler J, Merkel D, Kristal A, Caan B, Michaelson R, Vinciguerra V, Del Prete S, Winkler M, Hall R, Simon M, Winters BL, Elashoff RM (2006) Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women’s Intervention Nutrition Study. J Natl Cancer Inst 98(24):1767–1776. doi: 10.1093/jnci/djj494 PubMedCrossRefGoogle Scholar
  122. 122.
    van Rossum EF, Nicklas BJ, Dennis KE, Berman DM, Goldberg AP (2000) Leptin responses to weight loss in postmenopausal women: relationship to sex-hormone binding globulin and visceral obesity. Obes Res 8(1):29–35. doi: 10.1038/oby.2000.5 PubMedCrossRefGoogle Scholar
  123. 123.
    Imayama I, Ulrich CM, Alfano CM, Wang C, Xiao L, Wener MH, Campbell KL, Duggan C, Foster-Schubert KE, Kong A, Mason CE, Wang CY, Blackburn GL, Bain CE, Thompson HJ, McTiernan A (2012) Effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in overweight/obese postmenopausal women: a randomized controlled trial. Cancer Res 72(9):2314–2326. doi: 10.1158/0008-5472.CAN-11-3092 PubMedCrossRefGoogle Scholar
  124. 124.
    Esposito K, Pontillo A, Di Palo C, Giugliano G, Masella M, Marfella R, Giugliano D (2003) Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA 289(14):1799–1804. doi: 10.1001/jama.289.14.1799 PubMedCrossRefGoogle Scholar
  125. 125.
    Bastard JP, Jardel C, Bruckert E, Blondy P, Capeau J, Laville M, Vidal H, Hainque B (2000) Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin Endocrinol Metab 85(9):3338–3342PubMedCrossRefGoogle Scholar
  126. 126.
    Brown KA, Hunger NI, Docanto M, Simpson ER (2010) Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase. Breast Cancer Res Treat 123(2):591–596. doi: 10.1007/s10549-010-0834-y PubMedCrossRefGoogle Scholar
  127. 127.
    Samarajeewa NU, Ham S, Yang F, Simpson ER, Brown KA (2011) Promoter-specific effects of metformin on aromatase transcript expression. Steroids 76(8):768–771. doi: 10.1016/j.steroids.2011.02.041 PubMedCrossRefGoogle Scholar
  128. 128.
    Goodwin PJ, Pritchard KI, Ennis M, Clemons M, Graham M, Fantus IG (2008) Insulin-­lowering effects of metformin in women with early breast cancer. Clin Breast Cancer 8(6):501–505. doi: 10.3816/CBC.2008.n.060 PubMedCrossRefGoogle Scholar
  129. 129.
    Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, Hsu L, Hung MC, Hortobagyi GN, Gonzalez-Angulo AM (2009) Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 27(20):3297–3302. doi: 10.1200/JCO.2009.19.6410 PubMedCrossRefGoogle Scholar
  130. 130.
    Dannenberg AJ, Altorki NK, Boyle JO, Dang C, Howe LR, Weksler BB, Subbaramaiah K (2001) Cyclo-oxygenase 2: a pharmacological target for the prevention of cancer. Lancet Oncol 2(9):544–551. doi: 10.1016/S1470-2045(01)00488-0 PubMedCrossRefGoogle Scholar
  131. 131.
    Howe LR, Subbaramaiah K, Brown AM, Dannenberg AJ (2001) Cyclooxygenase-2: a target for the prevention and treatment of breast cancer. Endocr Relat Cancer 8(2):97–114PubMedCrossRefGoogle Scholar
  132. 132.
    Flossmann E, Rothwell PM (2007) Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 369(9573):1603–1613. doi: 10.1016/S0140-6736(07)60747-8 PubMedCrossRefGoogle Scholar
  133. 133.
    Howe LR (2007) Inflammation and breast cancer. Cyclooxygenase/prostaglandin signaling and breast cancer. Breast Cancer Res 9(4):210PubMedCrossRefGoogle Scholar
  134. 134.
    Zhang X, Smith-Warner SA, Collins LC, Rosner B, Willett WC, Hankinson SE (2012) Use of aspirin, other nonsteroidal anti-inflammatory drugs, and acetaminophen and postmenopausal breast cancer incidence. J Clin Oncol 30(28):3468–3477. ­doi: 10.1200/JCO.2012.42.2006 PubMedCrossRefGoogle Scholar
  135. 135.
    Terry MB, Gammon MD, Zhang FF, Tawfik H, Teitelbaum SL, Britton JA, Subbaramaiah K, Dannenberg AJ, Neugut AI (2004) Association of frequency and duration of aspirin use and hormone receptor status with breast cancer risk. JAMA 291(20):2433–2440. doi: 10.1001/jama.291.20.2433 PubMedCrossRefGoogle Scholar
  136. 136.
    Takkouche B, Regueira-Mendez C, Etminan M (2008) Breast cancer and use of nonsteroidal anti-inflammatory drugs: a meta-analysis. J Natl Cancer Inst 100(20):1439–1447. doi: 10.1093/jnci/djn324 PubMedCrossRefGoogle Scholar
  137. 137.
    Hudis CA, Subbaramaiah K, Morris PG, Dannenberg AJ (2012) Breast cancer risk reduction: no pain, no gain? J Clin Oncol 30(28):3436–3438. doi: 10.1200/JCO.2012.44.8597 PubMedCrossRefGoogle Scholar
  138. 138.
    Shellman YG, Ribble D, Miller L, Gendall J, Vanbuskirk K, Kelly D, Norris DA, Dellavalle RP (2005) Lovastatin-induced apoptosis in human melanoma cell lines. Melanoma Res 15(2):83–89PubMedCrossRefGoogle Scholar
  139. 139.
    Koyuturk M, Ersoz M, Altiok N (2004) Simvastatin induces proliferation inhibition and apoptosis in C6 glioma cells via c-jun N-terminal kinase. Neurosci Lett 370(2–3):212–217. doi: 10.1016/j.neulet.2004.08.020 PubMedCrossRefGoogle Scholar
  140. 140.
    Girgert R, Vogt Y, Becke D, Bruchelt G, Schweizer P (1999) Growth inhibition of neuroblastoma cells by lovastatin and L-ascorbic acid is based on different mechanisms. Cancer Lett 137(2):167–172PubMedCrossRefGoogle Scholar
  141. 141.
    Dimitroulakos J, Thai S, Wasfy GH, Hedley DW, Minden MD, Penn LZ (2000) Lovastatin induces a pronounced differentiation response in acute myeloid leukemias. Leuk Lymphoma 40(1–2):167–178. doi: 10.3109/10428190009054894 PubMedCrossRefGoogle Scholar
  142. 142.
    Kawata S, Yamasaki E, Nagase T, Inui Y, Ito N, Matsuda Y, Inada M, Tamura S, Noda S, Imai Y, Matsuzawa Y (2001) Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br J Cancer 84(7):886–891. doi: 10.1054/bjoc.2000.1716 PubMedCrossRefGoogle Scholar
  143. 143.
    Kim WS, Kim MM, Choi HJ, Yoon SS, Lee MH, Park K, Park CH, Kang WK (2001) Phase II study of high-dose lovastatin in patients with advanced gastric adenocarcinoma. Invest New Drugs 19(1):81–83PubMedCrossRefGoogle Scholar
  144. 144.
    Knox JJ, Siu LL, Chen E, Dimitroulakos J, Kamel-Reid S, Moore MJ, Chin S, Irish J, LaFramboise S, Oza AM (2005) A Phase I trial of prolonged administration of lovastatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or of the cervix. Eur J Cancer 41(4):523–530. doi: 10.1016/j.ejca.2004.12.013 PubMedCrossRefGoogle Scholar
  145. 145.
    Larner J, Jane J, Laws E, Packer R, Myers C, Shaffrey M (1998) A phase I-II trial of lovastatin for anaplastic astrocytoma and glioblastoma multiforme. Am J Clin Oncol 21(6):579–583PubMedCrossRefGoogle Scholar
  146. 146.
    Thibault A, Samid D, Tompkins AC, Fig. WD, Cooper MR, Hohl RJ, Trepel J, Liang B, Patronas N, Venzon DJ, Reed E, Myers CE (1996) Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clin Cancer Res 2(3):483–491PubMedGoogle Scholar
  147. 147.
    Periyasamy-Thandavan S, Takhar S, Singer A, Dohn MR, Jackson WH, Welborn AE, Leroith D, Marrero M, Thangaraju M, Huang S, Schoenlein PV (2012) Insulin-like growth factor 1 attenuates antiestrogen- and antiprogestin-induced apoptosis in ER+ breast cancer cells by MEK1 regulation of the BH3-only pro-apoptotic protein Bim. Breast Cancer Res 14(2):R52. doi: 10.1186/bcr3153 PubMedCrossRefGoogle Scholar
  148. 148.
    Sachdev D, Li SL, Hartell JS, Fujita-Yamaguchi Y, Miller JS, Yee D (2003) A chimeric humanized single-chain antibody against the type I insulin-like growth factor (IGF) receptor renders breast cancer cells refractory to the mitogenic effects of IGF-I. Cancer Res 63(3):627–635PubMedGoogle Scholar
  149. 149.
    Ye JJ, Liang SJ, Guo N, Li SL, Wu AM, Giannini S, Sachdev D, Yee D, Brunner N, Ikle D, Fujita-Yamaguchi Y (2003) Combined effects of tamoxifen and a chimeric humanized single chain antibody against the type I IGF receptor on breast tumor growth in vivo. Horm Metab Res 35(11–12):836–842. doi: 10.1055/s-2004-814145 PubMedGoogle Scholar
  150. 150.
    Sachdev D, Singh R, Fujita-Yamaguchi Y, Yee D (2006) Down-regulation of insulin receptor by antibodies against the type I insulin-like growth factor receptor: implications for ­anti-­insulin-like growth factor therapy in breast cancer. Cancer Res 66(4):2391–2402. doi: 10.1158/0008-5472.CAN-05-3126 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Neil M. Iyengar
    • 1
  • Patrick G. Morris
    • 1
  • Clifford A. Hudis
    • 1
  • Andrew J. Dannenberg
    • 2
    Email author
  1. 1.Memorial Sloan-Kettering Cancer CenterNew YorkUSA
  2. 2.Department of MedicineWeill Cornell Medical CollegeNew YorkUSA

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