Skip to main content

Advertisement

Log in

Deconvoluting the Obesity and Breast Cancer Link: Secretome, Soil and Seed Interactions

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Obesity is associated with increased risk of breast cancer in postmenopausal women and is linked with poor prognosis in pre- and postmenopausal breast cancer patients. The mechanisms underlying the obesity-breast cancer connection are becoming increasingly clear and provide multiple opportunities for primary to tertiary prevention. Several obesity-related host factors can influence breast tumor initiation, progression and/or response to therapy, and these have been implicated as key contributors to the complex effects of obesity on cancer incidence and outcomes. These host factors include components of the secretome, including insulin, insulin-like growth factor-1, leptin, adiponectin, steroid hormones, cytokines, vascular regulators, and inflammation-related molecules, as well as the cellular and structural components of the tumor microenvironment. These secreted and structural host factors are extrinsic to, and interact with, the intrinsic molecular characteristics of breast cancer cells (including breast cancer stem cells), and each will be considered in the context of energy balance and as potential targets for cancer prevention.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

Abbreviations

mTOR:

mammalian target of rapamycin

IGF-1:

Insulin-like growth factor-1

ER:

estrogen receptor

miRs:

microRNAs

References

  1. Finucane MM et al. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet. 2011;377(9765):557–67.

    Article  PubMed  Google Scholar 

  2. Flegal KM et al. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA. 2012;307(5):491–7.

    Article  PubMed  Google Scholar 

  3. Prevention, C.f.D.C.a. 2012; Available from: http://www.cdc.gov/nchs/fastats/bodymeas.htm.

  4. Available from: http://www.iaso.org/resources/obesity-data-portal/resources/charts/.

  5. Reeves GK et al. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. BMJ. 2007;335(7630):1134.

    Article  PubMed  Google Scholar 

  6. Yang XR et al. Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies. J Natl Cancer Inst. 2011;103(3):250–63.

    Article  PubMed  Google Scholar 

  7. Prat A et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res: BCR. 2010;12(5):R68.

    Article  PubMed  Google Scholar 

  8. Dogan S et al. Effects of high-fat diet and/or body weight on mammary tumor leptin and apoptosis signaling pathways in MMTV-TGF-alpha mice. Breast Cancer Res. 2007;9(6):R91.

    Article  PubMed  Google Scholar 

  9. Dunlap SM et al. Dietary energy balance modulates epithelial-to-mesenchymal transition and tumor progression in murine claudin-low and basal-like mammary tumor models. Cancer Prev Res. 2012;5(7):930–42.

    Article  CAS  Google Scholar 

  10. Giles ED et al. Obesity and overfeeding affecting both tumor and systemic metabolism activates the progesterone receptor to contribute to postmenopausal breast cancer. Cancer Res. 2012;72(24):6490–501.

    Article  PubMed  CAS  Google Scholar 

  11. Hakkak R et al. Obesity increases the incidence of 7,12-dimethylbenz(a)anthracene-induced mammary tumors in an ovariectomized Zucker rat model. Int J Oncol. 2007;30(3):557–63.

    PubMed  CAS  Google Scholar 

  12. Cleary MP et al. Diet-induced obesity and mammary tumor development in MMTV-neu female mice. Nutr Cancer. 2004;50(2):174–80.

    Article  PubMed  Google Scholar 

  13. Ford NA et al. IGF1 dependence of dietary energy balance effects on murine Met1 mammary tumor progression, epithelial-to-mesenchymal transition, and chemokine expression. Endocr-Relat Cancer. 2013;20(1):39–51.

    Article  PubMed  CAS  Google Scholar 

  14. Mizuno NK et al. Combination of intermittent calorie restriction and eicosapentaenoic acid for inhibition of mammary tumors. Cancer Prev Res. 2013;6(6):540–7.

    Article  CAS  Google Scholar 

  15. Hursting SD, Hursting MJ. Growth signals, inflammation, and vascular perturbations: mechanistic links between obesity, metabolic syndrome, and cancer. Arterioscler Thromb Vasc Biol. 2012;32(8):1766–70.

    Article  PubMed  CAS  Google Scholar 

  16. Makridakis M, Vlahou A. Secretome proteomics for discovery of cancer biomarkers. J Proteome. 2010;73(12):2291–305.

    Article  CAS  Google Scholar 

  17. Paget S. The distribution of secondary growths in cancer of the breast. Lancet. 1889;1:571–3.

    Article  Google Scholar 

  18. Brown KJ et al., The human secretome atlas initiative: Implications in health and disease conditions. Biochimica et Biophysica Acta, 2013.

  19. Place AE, Jin Huh S, Polyak K. The microenvironment in breast cancer progression: biology and implications for treatment. Breast Cancer Res. 2011;13(6):227.

    Article  PubMed  CAS  Google Scholar 

  20. Deng Y, Scherer PE. Adipokines as novel biomarkers and regulators of the metabolic syndrome. Ann N Y Acad Sci. 2010;1212:E1–19.

    Article  PubMed  Google Scholar 

  21. Karastergiou K, Mohamed-Ali V. The autocrine and paracrine roles of adipokines. Mol Cell Endocrinol. 2010;318(1–2):69–78.

    Article  PubMed  CAS  Google Scholar 

  22. Nam SY et al. Effect of obesity on total and free insulin-like growth factor (IGF)-1, and their relationship to IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3, insulin, and growth hormone. Int J Obes Relat Metab Disord. 1997;21(5):355–9.

    Article  PubMed  CAS  Google Scholar 

  23. Hursting SD et al., Calories and cancer: the role of insulin-like growth factor-1, in The IGF system and cancer, D. Leroith, Editor 2011, Springer, NY. p. 231–243.

  24. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008;8(12):915–28.

    Article  PubMed  CAS  Google Scholar 

  25. Wong KK, Engelman JA, Cantley LC. Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev. 2010;20(1):87–90.

    Article  PubMed  CAS  Google Scholar 

  26. Memmott RM, Dennis PA. Akt-dependent and -independent mechanisms of mTOR regulation in cancer. Cell Signal. 2009;21(5):656–64.

    Article  PubMed  CAS  Google Scholar 

  27. Moore T et al. Dietary energy balance modulates signaling through the Akt/mammalian target of rapamycin pathways in multiple epithelial tissues. Cancer Prev Res (Phila). 2008;1(1):65–76.

    Article  CAS  Google Scholar 

  28. De Angel RE 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(6):446–58.

    Article  PubMed  Google Scholar 

  29. Nogueira LM et al. Calorie restriction and rapamycin inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity. Endocr Relat Cancer. 2012;19(1):57–68.

    Article  PubMed  CAS  Google Scholar 

  30. Gautron L, Elmquist JK. Sixteen years and counting: an update on leptin in energy balance. J Clin Invest. 2011;121(6):2087–93.

    Article  PubMed  CAS  Google Scholar 

  31. Gross A et al., Adipocytokines, inflammation, and breast cancer risk in postmenopausal women: a prospective study. Cancer Epidemiol Biomarkers Prev, 2013.

  32. Wu MH et al. Circulating levels of leptin, adiposity and breast cancer risk. Br J Cancer. 2009;100(4):578–82.

    Article  PubMed  CAS  Google Scholar 

  33. Mantzoros CS et al. Leptin in relation to carcinoma in situ of the breast: a study of pre-menopausal cases and controls. Int J Cancer. 1999;80(4):523–6.

    Article  PubMed  CAS  Google Scholar 

  34. Petridou E et al. Leptin and insulin growth factor I in relation to breast cancer (Greece). Cancer Causes Control. 2000;11(5):383–8.

    Article  PubMed  CAS  Google Scholar 

  35. Stattin P et al. Plasma leptin and breast cancer risk: a prospective study in northern Sweden. Breast Cancer Res Treat. 2004;86(3):191–6.

    Article  PubMed  CAS  Google Scholar 

  36. Harris HR et al. Plasma leptin levels and risk of breast cancer in premenopausal women. Cancer Prev Res (Phila). 2011;4(9):1449–56.

    Article  CAS  Google Scholar 

  37. Cirillo D et al. Leptin signaling in breast cancer: an overview. J Cell Biochem. 2008;105(4):956–64.

    Article  PubMed  CAS  Google Scholar 

  38. Vaiopoulos AG et al. The role of adiponectin in human vascular physiology. Int J Cardiol. 2012;155(2):188–93.

    Article  PubMed  Google Scholar 

  39. Miyoshi Y et al. Association of serum adiponectin levels with breast cancer risk. Clin Cancer Res. 2003;9(15):5699–704.

    PubMed  CAS  Google Scholar 

  40. Mantzoros C et al. Adiponectin and breast cancer risk. J Clin Endocrinol Metab. 2004;89(3):1102–7.

    Article  PubMed  CAS  Google Scholar 

  41. Tian YF et al. Anthropometric measures, plasma adiponectin, and breast cancer risk. Endocr Relat Cancer. 2007;14(3):669–77.

    Article  PubMed  CAS  Google Scholar 

  42. Tworoger SS et al. Plasma adiponectin concentrations and risk of incident breast cancer. J Clin Endocrinol Metab. 2007;92(4):1510–6.

    Article  PubMed  CAS  Google Scholar 

  43. Barb D et al. Adiponectin in relation to malignancies: a review of existing basic research and clinical evidence. Am J Clin Nutr. 2007;86(3):s858–66.

    PubMed  Google Scholar 

  44. Stofkova A. Leptin and adiponectin: from energy and metabolic dysbalance to inflammation and autoimmunity. Endocr Regul. 2009;43(4):157–68.

    PubMed  CAS  Google Scholar 

  45. Renehan AG, Roberts DL, Dive C. Obesity and cancer: pathophysiological and biological mechanisms. Arch Physiol Biochem. 2008;114(1):71–83.

    Article  PubMed  CAS  Google Scholar 

  46. Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441(7092):431–6.

    Article  PubMed  CAS  Google Scholar 

  47. Del Prete A et al. Molecular pathways in cancer-related inflammation. Biochem Med (Zagreb). 2011;21(3):264–75.

    Article  Google Scholar 

  48. Chen DC et al. Serum adiponectin and leptin levels in Taiwanese breast cancer patients. Cancer Lett. 2006;237(1):109–14.

    Article  PubMed  CAS  Google Scholar 

  49. Ashizawa N et al. Serum leptin-adiponectin ratio and endometrial cancer risk in postmenopausal female subjects. Gynecol Oncol. 2010;119(1):65–9.

    Article  PubMed  CAS  Google Scholar 

  50. Cleary MP et al. Targeting the adiponectin: leptin ratio for postmenopausal breast cancer prevention. Front Biosci (Schol Ed). 2009;1:329–57.

    Google Scholar 

  51. Key TJ et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst. 2003;95(16):1218–26.

    Article  PubMed  CAS  Google Scholar 

  52. Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med. 2006;354(3):270–82.

    Article  PubMed  CAS  Google Scholar 

  53. Pequeux C et al. Stromal estrogen receptor-alpha promotes tumor growth by normalizing an increased angiogenesis. Cancer Res. 2012;72(12):3010–9.

    Article  PubMed  CAS  Google Scholar 

  54. Brodie AM, Marsh D, Brodie HJ. Aromatase inhibitors–IV. Regression of hormone-dependent, mammary tumors in the rat with 4-acetoxy-4-androstene-3,17-dione. J Steroid Biochem. 1979;10(4):423–9.

    Article  PubMed  CAS  Google Scholar 

  55. Basu S et al. Eicosanoids and adipokines in breast cancer: from molecular mechanisms to clinical considerations. Antioxid Redox Signal. 2013;18(3):323–60.

    Article  PubMed  CAS  Google Scholar 

  56. Harvey AE, Lashinger LM, Hursting SD. The growing challenge of obesity and cancer: an inflammatory issue. Ann N Y Acad Sci. 2011;1229:45–52.

    Article  PubMed  CAS  Google Scholar 

  57. Subbaramaiah K et al. Obesity is associated with inflammation and elevated aromatase expression in the mouse mammary gland. Cancer Prev Res (Phila). 2011;4(3):329–46.

    Article  CAS  Google Scholar 

  58. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219–46.

    Article  PubMed  CAS  Google Scholar 

  59. Ono M. Molecular links between tumor angiogenesis and inflammation: inflammatory stimuli of macrophages and cancer cells as targets for therapeutic strategy. Cancer Sci. 2008;99(8):1501–6.

    Article  PubMed  CAS  Google Scholar 

  60. Aggarwal BB, Gehlot P. Inflammation and cancer: how friendly is the relationship for cancer patients? Curr Opin Pharmacol. 2009;9(4):351–69.

    Article  PubMed  CAS  Google Scholar 

  61. Kundu JK, Surh YJ. Inflammation: gearing the journey to cancer. Mutat Res. 2008;659(1–2):15–30.

    PubMed  CAS  Google Scholar 

  62. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–7.

    Article  PubMed  CAS  Google Scholar 

  63. Charriere G et al. Preadipocyte conversion to macrophage. Evidence of plasticity. J Biol Chem. 2003;278(11):9850–5.

    Article  PubMed  CAS  Google Scholar 

  64. Allavena P et al. The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol. 2008;66(1):1–9.

    Article  PubMed  Google Scholar 

  65. Calabro P, Yeh ET. Obesity, inflammation, and vascular disease: the role of the adipose tissue as an endocrine organ. Subcell Biochem. 2007;42:63–91.

    Article  PubMed  Google Scholar 

  66. Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004;4(7):540–50.

    Article  PubMed  CAS  Google Scholar 

  67. Kulbe H et al. The chemokine network in cancer–much more than directing cell movement. Int J Dev Biol. 2004;48(5–6):489–96.

    Article  PubMed  CAS  Google Scholar 

  68. Allavena P et al. The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance. Immunol Rev. 2008;222:155–61.

    Article  PubMed  CAS  Google Scholar 

  69. Cao Y. Angiogenesis modulates adipogenesis and obesity. J Clin Invest. 2007;117(9):2362–8.

    Article  PubMed  CAS  Google Scholar 

  70. Byrne AM, Bouchier-Hayes DJ, Harmey JH. Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J Cell Mol Med. 2005;9(4):777–94.

    Article  PubMed  CAS  Google Scholar 

  71. Liu Y et al. The association between vascular endothelial growth factor expression in invasive breast cancer and survival varies with intrinsic subtypes and use of adjuvant systemic therapy: results from the Nurses’ Health Study. Breast Cancer Res Treat. 2011;129(1):175–84.

    Article  PubMed  CAS  Google Scholar 

  72. Chen CT et al. Targeting the IKKbeta/mTOR/VEGF signaling pathway as a potential therapeutic strategy for obesity-related breast cancer. Mol Cancer Ther. 2012;11(10):2212–21.

    Article  PubMed  CAS  Google Scholar 

  73. Iwaki T, Urano T, Umemura K. PAI-1, progress in understanding the clinical problem and its aetiology. Br J Haematol. 2012;157(3):291–8.

    Article  PubMed  CAS  Google Scholar 

  74. Carter JC, Church FC. Obesity and breast cancer: the roles of peroxisome proliferator-activated receptor-gamma and plasminogen activator inhibitor-1. PPAR Res. 2009;2009:345320.

    PubMed  Google Scholar 

  75. Skurk T, Hauner H. Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1. Int J Obes Relat Metab Disord. 2004;28(11):1357–64.

    Article  PubMed  CAS  Google Scholar 

  76. Muldowney 3rd JA et al. Pentoxifylline lowers plasminogen activator inhibitor 1 levels in obese individuals: a pilot study. Angiology. 2012;63(6):429–34.

    Article  PubMed  Google Scholar 

  77. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  PubMed  CAS  Google Scholar 

  78. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.

    Article  PubMed  CAS  Google Scholar 

  79. Hollstein M et al. p53 mutations in human cancers. Science. 1991;253(5015):49–53.

    Article  PubMed  CAS  Google Scholar 

  80. Molchadsky A et al. p53 is required for brown adipogenic differentiation and has a protective role against diet-induced obesity. Cell Death Differ. 2013;20(5):774–83.

    Article  PubMed  CAS  Google Scholar 

  81. Park H et al. A high-fat diet increases angiogenesis, solid tumor growth, and lung metastasis of CT26 colon cancer cells in obesity-resistant BALB/c mice. Mol Carcinog. 2012;51(11):869–80.

    Article  PubMed  CAS  Google Scholar 

  82. Dhasarathy A, Kajita M, Wade PA. The transcription factor snail mediates epithelial to mesenchymal transitions by repression of estrogen receptor-alpha. Mol Endocrinol. 2007;21(12):2907–18.

    Article  PubMed  CAS  Google Scholar 

  83. Liu G, Schwartz JA, Brooks SC. Estrogen receptor protects p53 from deactivation by human double minute-2. Cancer Res. 2000;60(7):1810–4.

    PubMed  CAS  Google Scholar 

  84. Hurd C et al. Estrogen-dependent and independent activation of the P1 promoter of the p53 gene in transiently transfected breast cancer cells. Oncogene. 1999;18(4):1067–72.

    Article  PubMed  CAS  Google Scholar 

  85. Konduri SD et al. Mechanisms of estrogen receptor antagonism toward p53 and its implications in breast cancer therapeutic response and stem cell regulation. Proc Natl Acad Sci U S A. 2010;107(34):15081–6.

    Article  PubMed  CAS  Google Scholar 

  86. Shirley SH et al. Transcriptional regulation of estrogen receptor-alpha by p53 in human breast cancer cells. Cancer Res. 2009;69(8):3405–14.

    Article  PubMed  CAS  Google Scholar 

  87. Zhang X et al. Estrogen receptor positivity in mammary tumors of Wnt-1 transgenic mice is influenced by collaborating oncogenic mutations. Oncogene. 2005;24(26):4220–31.

    Article  PubMed  CAS  Google Scholar 

  88. Fuchs-Young R et al. P53 genotype as a determinant of ER expression and tamoxifen response in the MMTV-Wnt-1 model of mammary carcinogenesis. Breast Cancer Res Treat. 2011;130(2):399–408.

    Article  PubMed  CAS  Google Scholar 

  89. Freeman EW et al. Obesity and reproductive hormone levels in the transition to menopause. Menopause. 2010;17(4):718–26.

    Article  PubMed  Google Scholar 

  90. Wolff AC et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2007;131(1):18–43.

    PubMed  CAS  Google Scholar 

  91. Skliris GP et al. Reduced expression of oestrogen receptor beta in invasive breast cancer and its re-expression using DNA methyl transferase inhibitors in a cell line model. J Pathol. 2003;201(2):213–20.

    Article  PubMed  CAS  Google Scholar 

  92. Luo J et al. A comparison of batch effect removal methods for enhancement of prediction performance using MAQC-II microarray gene expression data. Pharmacogenomics J. 2010;10(4):278–91.

    Article  PubMed  CAS  Google Scholar 

  93. Wang ZV et al. Identification and characterization of a promoter cassette conferring adipocyte-specific gene expression. Endocrinology. 2010;151(6):2933–9.

    Article  PubMed  CAS  Google Scholar 

  94. Karastergiou K et al. Epicardial adipokines in obesity and coronary artery disease induce atherogenic changes in monocytes and endothelial cells. Arterioscler Thromb Vasc Biol. 2010;30(7):1340–6.

    Article  PubMed  CAS  Google Scholar 

  95. Kalaany NY, Sabatini DM. Tumours with PI3K activation are resistant to dietary restriction. Nature. 2009;458(7239):725–31.

    Article  PubMed  CAS  Google Scholar 

  96. Elkabets M et al. mTORC1 inhibition is required for sensitivity to PI3K p110alpha Inhibitors in PIK3CA-mutant breast cancer. Sci Trans Med. 2013;5(196):196ra99.

    Article  CAS  Google Scholar 

  97. Njiaju UO, Olopade OI. Genetic determinants of breast cancer risk: a review of current literature and issues pertaining to clinical application. Breast J. 2012;18(5):436–42.

    Article  PubMed  CAS  Google Scholar 

  98. Ford NA et al. Obesity, independent of p53 gene dosage, promotes mammary tumor progression and upregulates the p53 regulator MicroRNA-504. PLoS One. 2013;8(6):e68089.

    Article  PubMed  CAS  Google Scholar 

  99. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15(9):1010–2.

    Article  PubMed  CAS  Google Scholar 

  100. Velasco-Velazquez MA et al. Breast cancer stem cells. Int J Biochem Cell Biol. 2012;44(4):573–7.

    Article  PubMed  CAS  Google Scholar 

  101. Zheng Q et al. Leptin deficiency suppresses MMTV-Wnt-1 mammary tumor growth in obese mice and abrogates tumor initiating cell survival. Endocr Relat Cancer. 2011;18(4):491–503.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

SDH is funded, in part, by grants from the National Cancer Institute (R01CA129409 and R01CA135306), the Breast Cancer Research Foundation (UTA09-001068), and the National Institute of Environmental Health Sciences (P30ES007784). NAF was supported by an American Institute for Cancer Research Postdoctoral Fellowship and KLD was supported by a predoctoral fellowship from the National Institute of Environmental Health Sciences (T32ES07247).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stephen D. Hursting.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ford, N.A., Devlin, K.L., Lashinger, L.M. et al. Deconvoluting the Obesity and Breast Cancer Link: Secretome, Soil and Seed Interactions. J Mammary Gland Biol Neoplasia 18, 267–275 (2013). https://doi.org/10.1007/s10911-013-9301-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10911-013-9301-9

Keywords

Navigation