The Impact of Obesity on Breast Cancer
- 888 Downloads
The rates of obesity are increasing worldwide and this condition is now recognized as a leading preventable cause of cancer. Several diseases are directly related to obesity, including diabetes, hypertension, atherosclerosis, stroke, musculoskeletal disorders, and a diverse range of malignances—such as breast cancer. Obesity is associated with an increased risk of postmenopausal estrogen receptor-positive breast cancer and worse cancer-related outcomes for all breast tumor subtypes. Several mechanisms have been proposed to contribute to the obesity-cancer link, including high levels of circulating and local estrogens, altered amounts of adipokines (leptin and adiponectin), disrupted insulin/IGF signaling, modifications within the microbiome, and local and systemic effects of inflammation. Here we will review recent advances in our understanding of the complex signaling pathways underlying the obesity-cancer link. An improved understanding of these processes is anticipated to propel novel and effective intervention strategies to reduce the global obesity-cancer burden.
KeywordsObesity Inflammation Adipose tissue Insulin Metabolic syndrome Breast cancer
Compliance with Ethical Standards
Conflict of Interest
Daniel F. Argolo, Clifford A. Hudis, and Neil M. Iyengar declare they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults—the evidence report. National Institutes of Health. Obes Res. 1998;6 Suppl 2:51S–209S.Google Scholar
- 2.Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden0020of Disease Study 2013. Lancet. 2014;384(9945):766–81. https://doi.org/10.1016/S0140-6736(14)60460-8.CrossRefPubMedPubMedCentralGoogle Scholar
- 5.Adult obesity facts. Center for Disease Control and Prevention (CDC). Accessed 02/12/2017.Google Scholar
- 6.Emerging Risk Factors C, Wormser D, Kaptoge S, Di Angelantonio E, Wood AM, Pennells L, et al. Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies. Lancet. 2011;377(9771):1085–95. https://doi.org/10.1016/S0140-6736(11)60105-0.CrossRefGoogle Scholar
- 8.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. doi: https://doi.org/10.1200/EdBook_AM.2013.33.46.
- 13.Chan DS, Vieira AR, Aune D, Bandera EV, Greenwood DC, McTiernan A, et al. Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol. 2014;25(10):1901–14. https://doi.org/10.1093/annonc/mdu042.CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Kaaks R, Rinaldi S, Key TJ, Berrino F, Peeters PH, Biessy C, et al. Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocr Relat Cancer. 2005;12(4):1071–82. https://doi.org/10.1677/erc.1.01038.CrossRefPubMedGoogle Scholar
- 35.Bezemer ID, Rinaldi S, Dossus L, Gils CH, Peeters PH, Noord PA, et al. C-peptide, IGF-I, sex-steroid hormones and adiposity: a cross-sectional study in healthy women within the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes Control. 2005;16(5):561–72. https://doi.org/10.1007/s10552-004-7472-9.CrossRefPubMedGoogle Scholar
- 48.Iyengar NM, Morris PG, Hudis CA, Dannenberg AJ. Obesity, inflammation, and breast cancer. Obese, inflammation and breast cancer: Springer; 2013.Google Scholar
- 52.Kwa M, Plottel CS, Blaser MJ, Adams S. The intestinal microbiome and estrogen receptor-positive female breast cancer. J Natl Cancer Inst. 2016;108(8). doi: https://doi.org/10.1093/jnci/djw029.
- 53.Goedert JJ, Jones G, Hua X, Xu X, Yu G, Flores R et al. Investigation of the association between the fecal microbiota and breast cancer in postmenopausal women: a population-based case-control pilot study. J Natl Cancer Inst. 2015;107(8). doi: https://doi.org/10.1093/jnci/djv147.
- 57.Morris PG, Zhou XK, Milne GL, Goldstein D, Hawks LC, Dang CT, et al. Increased levels of urinary PGE-M, a biomarker of inflammation, occur in association with obesity, aging, and lung metastases in patients with breast cancer. Cancer Prev Res. 2013;6(5):428–36. https://doi.org/10.1158/1940-6207.CAPR-12-0431.CrossRefGoogle Scholar
- 59.• Iyengar NM, Zhou XK, Gucalp A, Morris PG, Howe LR, Giri DD, et al. Systemic correlates of white adipose tissue inflammation in early-stage breast cancer. Clin Cancer Res. 2016;22(9):2283–9. https://doi.org/10.1158/1078-0432.CCR-15-2239. This study provided the first evidence that women with early-stage breast cancer and white adipose tissue inflammation in the breast have worse clinical outcomes than those without inflammation. The adjusted hazard ratio for distant recurrence-free survival was 1.83 (95% CI 1.07 to 3.13) for women with versus those without inflammation. CrossRefPubMedGoogle Scholar
- 60.•• Koru-Sengul T, Santander AM, Miao F, Sanchez LG, Jorda M, Gluck S, et al. Breast cancers from black women exhibit higher numbers of immunosuppressive macrophages with proliferative activity and of crown-like structures associated with lower survival compared to non-black Latinas and Caucasians. Breast cancer research and treatment. 2016;158(1):113–26. https://doi.org/10.1007/s10549-016-3847-3. This study confirmed the observation that white adipose inflammation in the breast is associated with worsened survival for women with breast cancer. Furthermore, this study identified racial disparities consistent with breast cancer epidemiologic observations. The highest prevalance of breast white adipose inflammation was found in black women verus non-black Latina and Caucasian women. CrossRefPubMedPubMedCentralGoogle Scholar
- 62.Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219–46. https://doi.org/10.1146/annurev-physiol-021909-135846.CrossRefPubMedGoogle Scholar
- 63.Murano I, Barbatelli G, Parisani V, Latini C, Muzzonigro G, Castellucci M, et al. Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J Lipid Res. 2008;49(7):1562–8. https://doi.org/10.1194/jlr.M800019-JLR200.CrossRefPubMedGoogle Scholar
- 65.Hardy DB, Janowski BA, Chen CC, Mendelson CR. Progesterone receptor inhibits aromatase and inflammatory response pathways in breast cancer cells via ligand-dependent and ligand-independent mechanisms. Mol Endocrinol. 2008;22(8):1812–24. https://doi.org/10.1210/me.2007-0443.CrossRefPubMedPubMedCentralGoogle Scholar
- 66.Irahara N, Miyoshi Y, Taguchi T, Tamaki Y, Noguchi S. 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. 2006;118(8):1915–21. https://doi.org/10.1002/ijc.21562.CrossRefPubMedGoogle Scholar
- 67.Salama SA, Kamel MW, Diaz-Arrastia CR, Xu X, Veenstra TD, Salih S, et al. Effect of tumor necrosis factor-alpha on estrogen metabolism and endometrial cells: potential physiological and pathological relevance. J Clin Endocrinol Metab. 2009;94(1):285–93. https://doi.org/10.1210/jc.2008-1389.CrossRefPubMedGoogle Scholar
- 69.Zhao Y, Agarwal VR, Mendelson CR, Simpson ER. 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. 1996;137(12):5739–42. https://doi.org/10.1210/endo.137.12.8940410.CrossRefPubMedGoogle Scholar
- 71.Zhao Y, Nichols JE, Valdez R, Mendelson CR, Simpson ER. Tumor necrosis factor-alpha stimulates aromatase gene expression in human adipose stromal cells through use of an activating protein-1 binding site upstream of promoter 1.4. Mol Endocrinol. 1996;10(11):1350–7. https://doi.org/10.1210/mend.10.11.8923461.PubMedGoogle Scholar
- 72.Mullooly M, Yang HP, Falk RT, Nyante SJ, Cora R, Pfeiffer RM, et al. Relationship between crown-like structures and sex-steroid hormones in breast adipose tissue and serum among postmenopausal breast cancer patients. Breast Cancer Res. 2017;19:8. https://doi.org/10.1186/s13058-016-0791-4.CrossRefPubMedPubMedCentralGoogle Scholar
- 73.Iyengar NM, Morris PG, Zhou XK, Gucalp A, Giri D, Harbus MD, et al. Menopause is a determinant of breast adipose inflammation. Cancer Prev Res. 2015; https://doi.org/10.1158/1940-6207.CAPR-14-0243.
- 74.•• Carter JM, Hoskin TL, Pena MA, Brahmbhatt R, Winham SJ, Frost MH, et al. Macrophagic “crown-like structures” are associated with an increased risk of breast cancer in benign breast disease. Cancer Prev Res. 2017; https://doi.org/10.1158/1940-6207.capr-17-0245. This is the first study to demonstrate that breast white adipose tissue inflammation is associated with breast cancer risk. Breast white adipose tissue inflammation was more prevalent in women with benign breast disease versus normal tissue donors. Among women with benign breast disease, the severity of breast white adipose tissue inflammation was higher in women who went on to develop breast cancer versus those who did not develop cancer.
- 75.• Iyengar NM, Brown KA, Zhou XK, Gucalp A, Subbaramaiah K, Giri DD, et al. Metabolic obesity, adipose inflammation and elevated breast aromatase in women with normal body mass index. Cancer Prev Res (Phila). 2017;10(4):235–43. https://doi.org/10.1158/1940-6207.CAPR-16-0314. In this study, a subclinical inflammatory state was identified in a subset of women with normal body mass index. Women with normal BMI and breast white adipose tissue inflammation had elevated levels of aromatase in the breast and systemic metabolic dysfunction compared to women without inflammation. These findings indicate that anthropometric indices such as BMI fail to identify some women with metabolic obesity and breast inflammation which can predispose to the development of breast cancer. CrossRefGoogle Scholar
- 77.Fischer JP, Cleveland EC, Nelson JA, Kovach SJ, Serletti JM, Wu LC, et al. Breast reconstruction in the morbidly obese patient: assessment of 30-day complications using the 2005 to 2010 National Surgical Quality Improvement Program data sets. Plast Reconstr Surg. 2013;132(4):750–61. https://doi.org/10.1097/PRS.0b013e31829fe33c.CrossRefPubMedGoogle Scholar
- 80.Fischer JP, Wes AM, Tuggle CT, Wu LC. Venous thromboembolism risk in mastectomy and immediate breast reconstruction: analysis of the 2005 to 2011 American College of Surgeons National Surgical Quality Improvement Program data sets. Plast Reconstr Surg. 2014;133(3):263e–73e. https://doi.org/10.1097/01.prs.0000438062.53914.22.CrossRefPubMedGoogle Scholar
- 83.Griggs JJ, Mangu PB, Anderson H, Balaban EP, Dignam JJ, Hryniuk WM, et al. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2012;30(13):1553–61. https://doi.org/10.1200/JCO.2011.39.9436.CrossRefPubMedGoogle Scholar
- 85.Rosner GL, Hargis JB, Hollis DR, Budman DR, Weiss RB, Henderson IC, et al. 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. 1996;14(11):3000–8. https://doi.org/10.1200/JCO.1922.214.171.12400.CrossRefPubMedGoogle Scholar
- 88.Pfeiler G, Konigsberg R, Fesl C, Mlineritsch B, Stoeger H, Singer CF, et al. Impact of body mass index on the efficacy of endocrine therapy in premenopausal patients with breast cancer: an analysis of the prospective ABCSG-12 trial. J Clin Oncol. 2011;29(19):2653–9. https://doi.org/10.1200/JCO.2010.33.2585.CrossRefPubMedGoogle Scholar
- 89.Ewertz M, Gray KP, Regan MM, Ejlertsen B, Price KN, Thurlimann B, et al. Obesity and risk of recurrence or death after adjuvant endocrine therapy with letrozole or tamoxifen in the breast international group 1-98 trial. J Clin Oncol. 2012;30(32):3967–75. https://doi.org/10.1200/JCO.2011.40.8666.CrossRefPubMedPubMedCentralGoogle Scholar
- 92.Goldsmith C, Haviland J, Tsang Y, Sydenham M, Yarnold J. Large breast size as a risk factor for late adverse effects of breast radiotherapy: is residual dose inhomogeneity, despite 3D treatment planning and delivery, the main explanation? Radiotherapy and Oncology. 100(2):236–40. https://doi.org/10.1016/j.radonc.2010.12.012.
- 93.Hardee ME, Raza S, Becker SJ, Jozsef G, Lymberis SC, Hochman T et al. Prone hypofractionated whole-breast radiotherapy without a boost to the tumor bed: comparable toxicity of IMRT versus a 3D conformal technique. Int J Radiat Oncol Biol Physics.82(3):e415-e23. doi: https://doi.org/10.1016/j.ijrobp.2011.06.1950.