Top

Published in:

01-08-2018 | Original Paper

Adiposity Results in Metabolic and Inflammation Differences in Premenopausal and Postmenopausal Women Consistent with the Difference in Breast Cancer Risk

Authors: H. Zhao, J. Wang, D. Fang, O. Lee, R. T. Chatterton, V. Stearns, S. A. Khan, S. E. Bulun

Published in: Discover Oncology | Issue 4/2018

Abstract

Obesity is associated with increased risk of breast cancer in postmenopausal but not in premenopausal women. Many factors may be responsible for this difference. The aim of this study was to determine the mechanisms by which the genes related to the AMPK pathway, inflammation, and estrogen actions are affected by adiposity in breast tissue with the objective of identifying differences that may explain the different breast cancer risk in premenopausal and postmenopausal women. Random fine needle aspirates (rFNAs) of breast tissue were collected from 57 premenopausal and 55 postmenopausal women and were classified as normal weight, overweight, or obese. Expression levels of 21 target genes were determined using a TaqMan Low Density Array procedure. Breast tissue estradiol levels were measured by a liquid chromatography-tandem mass spectrometry procedure, and serum estradiol and follicle-stimulating hormone (FSH) were measured by a radioimmunoassay and an enzyme-linked immunosorbent assay, respectively. We found that in postmenopausal women, serum and tissue estradiol levels were increased in those who were overweight, and serum FSH levels were decreased in obese status. Interestingly, RPS6KB1, an AMPK downstream-responsive gene for protein synthesis and cell growth, and estrogen receptor α (encoded by the ESR1 gene) and its target gene GATA3 were significantly decreased in rFNA of premenopausal, obese women. In postmenopausal women, RPS6KB1, ESR1, and GATA3 expression remained unchanged in relation to adiposity. However, prostaglandin-endoperoxide synthase 2 (PTGS2), cyclin D1 (CCND1), and another ESR1 target gene, TFF1, were elevated in rFNA of obese postmenopausal women. Thus, as bodyweight increases, gene expression is indicative of increased proliferation in postmenopausal women but decreased proliferation in premenopausal women. Overall, our data reveal a novel process by which obesity promotes the risk of breast cancer in postmenopausal but not premenopausal women.

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. https://doi.org/10.1016/S0140-6736(11)60814-3 CrossRefPubMed

Brown KA, Simpson ER (2010) Obesity and breast cancer: progress to understanding the relationship. Cancer Res 70(1):4–7. https://doi.org/10.1158/0008-5472.CAN-09-2257 CrossRefPubMed

Bulun SE, Chen D, Moy I, Brooks DC, Zhao H (2012) Aromatase, breast cancer and obesity: a complex interaction. Trends Endocrinol Metab 23(2):83–89. https://doi.org/10.1016/j.tem.2011.10.003 CrossRefPubMed

Cleary MP, Grossmann ME (2009) Mini review: obesity and breast cancer: the estrogen connection. Endocrinology 150(6):2537–2542. https://doi.org/10.1210/en.2009-0070 CrossRefPubMedPubMedCentral

Bianchini F, Kaaks R, Vainio H (2002) Overweight, obesity, and cancer risk. Lancet Oncol 3(9):565–574CrossRefPubMed

Bulun SE, Lin Z, Zhao H, Lu M, Amin S, Reierstad S, Chen D (2009) Regulation of aromatase expression in breast cancer tissue. Ann N Y Acad Sci 1155:121–131. https://doi.org/10.1111/j.1749-6632.2009.03705.x CrossRefPubMed

Bulun SE, Sharda G, Rink J, Sharma S, Simpson ER (1996) Distribution of aromatase P450 transcripts and adipose fibroblasts in the human breast. J Clin Endocrinol Metab 81(3):1273–1277PubMed

Chetrite GS, Cortes-Prieto J, Philippe JC, Wright F, Pasqualini JR (2000) Comparison of estrogen concentrations, estrone sulfatase and aromatase activities in normal, and in cancerous, human breast tissues. J Steroid Biochem Mol Biol 72(1–2):23–27CrossRefPubMed

Brown KA, McInnes KJ, Hunger NI, Oakhill JS, Steinberg GR, Simpson ER (2009) 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 69(13):5392–5399CrossRefPubMed

10.

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. https://doi.org/10.1158/1940-6207.CAPR-11-0110 CrossRef

11.

Subbaramaiah K, Morris PG, Zhou XK, Morrow M, Du B, Giri D et al (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. https://doi.org/10.1158/2159-8290.CD-11-0241 CrossRefPubMedPubMedCentral

12.

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. https://doi.org/10.1007/s10549-011-1789-3 CrossRefPubMed

13.

Brown KA, Samarajeewa NU, Simpson ER (2013) Endocrine-related cancers and the role of AMPK. Mol Cell Endocrinol 366(2):170–179. https://doi.org/10.1016/j.mce.2012.06.016 CrossRefPubMed

14.

Thompson AM (2014) Molecular pathways: preclinical models and clinical trials with metformin in breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 20(10):2508–2515. https://doi.org/10.1158/1078-0432.CCR-13-0354 CrossRef

15.

Shackelford DB, Shaw RJ (2009) The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 9(8):563–575. https://doi.org/10.1038/nrc2676 CrossRefPubMedPubMedCentral

16.

Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310(5754):1642–1646. https://doi.org/10.1126/science.1120781 CrossRefPubMedPubMedCentral

17.

Shaw RJ, Cantley LC (2006) Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441(7092):424–430. https://doi.org/10.1038/nature04869 CrossRefPubMed

18.

Hardie DG (2011) AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev 25(18):1895–1908. https://doi.org/10.1101/gad.17420111 CrossRefPubMedPubMedCentral

19.

Hoh J, Jin S, Parrado T, Edington J, Levine AJ, Ott J (2002) The p53MH algorithm and its application in detecting p53-responsive genes. Proc Natl Acad Sci U S A 99(13):8467–8472. https://doi.org/10.1073/pnas.132268899 CrossRefPubMedPubMedCentral

20.

Feng Z, Hu W, de Stanchina E, Teresky AK, Jin S, Lowe S, Levine AJ (2007) The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res 67(7):3043–3053. https://doi.org/10.1158/0008-5472.CAN-06-4149 CrossRefPubMed

21.

Metallo CM, Walther JL, Stephanopoulos G (2009) Evaluation of 13C isotopic tracers for metabolic flux analysis in mammalian cells. J Biotechnol 144(3):167–174. https://doi.org/10.1016/j.jbiotec.2009.07.010 CrossRefPubMedPubMedCentral

22.

Davies SP, Carling D, Munday MR, Hardie DG (1992) Diurnal rhythm of phosphorylation of rat liver acetyl-CoA carboxylase by the AMP-activated protein kinase, demonstrated using freeze-clamping. Effects of high fat diets. Eur J Biochem 203(3):615–623CrossRefPubMed

23.

Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G et al (2010) Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 120(7):2355–2369. https://doi.org/10.1172/JCI40671 CrossRefPubMedPubMedCentral

24.

Leclerc I, Kahn A, Doiron B (1998) The 5'-AMP-activated protein kinase inhibits the transcriptional stimulation by glucose in liver cells, acting through the glucose response complex. FEBS Lett 431(2):180–184CrossRefPubMed

25.

Rouzer CA, Marnett LJ (2009) Cyclooxygenases: structural and functional insights. J Lipid Res 50:Suppl:S29–Suppl:S34. https://doi.org/10.1194/jlr.R800042-JLR200 CrossRefPubMed

26.

Flower RJ (2003) The development of COX2 inhibitors. Nat Rev Drug Discov 2(3):179–191. https://doi.org/10.1038/nrd1034 CrossRefPubMed

27.

Howe LR (2007) Inflammation and breast cancer. Cyclooxygenase/prostaglandin signaling and breast cancer. Breast Cancer Res 9(4):210CrossRefPubMedPubMedCentral

28.

Kochel TJ, Goloubeva OG, Fulton AM (2016) Upregulation of cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) pathway member multiple drug resistance-associated protein 4 (MRP4) and downregulation of prostaglandin transporter (PGT) and 15-prostaglandin dehydrogenase (15-PGDH) in triple-negative breast cancer. Breast Cancer (Auckl) 10:61–70. https://doi.org/10.4137/BCBCR.S38529 CrossRef

29.

van Kruijsdijk RC, van der Wall E, Visseren FL (2009) Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomark Prev 18(10):2569–2578. https://doi.org/10.1158/1055-9965.EPI-09-0372 CrossRef

30.

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):514–527CrossRefPubMed

31.

Stearns V, Fackler MJ, Hafeez S, Lopez Bujanda Z, Chatterton RT, Jacobs LK et al (2016) Gene methylation and cytological atypia in random fine needle aspirates for assessment of breast cancer risk. Cancer Prev Res (Phila). https://doi.org/10.1158/1940-6207.CAPR-15-0377

32.

Deb S, Amin S, Imir AG, Yilmaz MB, Suzuki T, Sasano H, Bulun SE (2004) Estrogen regulates expression of tumor necrosis factor receptors in breast adipose fibroblasts. J Clin Endocrinol Metab 89(8):4018–4024. https://doi.org/10.1210/jc.2004-0127 CrossRefPubMed

33.

Sletten A, Seline A, Rudd A, Logsdon M, Listenberger LL (2014) Surface features of the lipid droplet mediate perilipin 2 localization. Biochem Biophys Res Commun. https://doi.org/10.1016/j.bbrc.2014.08.097

34.

John EM, Sangaramoorthy M, Hines LM, Stern MC, Baumgartner KB, Giuliano AR, Wolff RK, Slattery ML (2014) Overall and abdominal adiposity and premenopausal breast cancer risk among Hispanic women: the breast cancer health disparities study. Cancer Epidemiol Biomark Prev. https://doi.org/10.1158/1055-9965.EPI-13-1007-T

35.

Carmichael AR, Bates T (2004) Obesity and breast cancer: a review of the literature. Breast 13(2):85–92. https://doi.org/10.1016/j.breast.2003.03.001 CrossRefPubMed

36.

Bandera EV, Chandran U, Hong CC, Troester MA, Bethea TN, Adams-Campbell LL, Haiman CA, Park SY, Olshan AF, Ambrosone CB, Palmer JR, Rosenberg L (2015) Obesity, body fat distribution, and risk of breast cancer subtypes in African American women participating in the AMBER Consortium. Breast Cancer Res Treat 150(3):655–666. https://doi.org/10.1007/s10549-015-3353-z CrossRefPubMedPubMedCentral

37.

Cleary MP, Grossmann ME (2009) Minireview: Obesity and breast cancer: the estrogen connection. Endocrinology 150(6):2537–2542CrossRefPubMedPubMedCentral

38.

Isakson P, Hammarstedt A, Gustafson B, Smith U (2009) Impaired preadipocyte differentiation in human abdominal obesity: role of Wnt, tumor necrosis factor-alpha, and inflammation. Diabetes 58(7):1550–1557. https://doi.org/10.2337/db08-1770 CrossRefPubMedPubMedCentral

39.

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, Key TJ, 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, Longcope C, Endogenous Hormones Breast Cancer Collaborative Group (2003) Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 95(16):1218–1226CrossRefPubMed

40.

Judd HL, Lucas WE, Yen SS (1976) Serum 17 beta-estradiol and estrone levels in postmenopausal women with and without endometrial cancer. J Clin Endocrinol Metab 43(2):272–278. https://doi.org/10.1210/jcem-43-2-272 CrossRefPubMed

41.

Kaul G, Pattan G, Rafeequi T (2011) Eukaryotic elongation factor-2 (eEF2): its regulation and peptide chain elongation. Cell Biochem Funct 29(3):227–234. https://doi.org/10.1002/cbf.1740 CrossRefPubMed

42.

Hayashi AA, Nones K, Roy NC, McNabb WC, Mackenzie DS, Pacheco D et al (2009) Initiation and elongation steps of mRNA translation are involved in the increase in milk protein yield caused by growth hormone administration during lactation. J Dairy Sci 92(5):1889–1899. https://doi.org/10.3168/jds.2008-1334 CrossRefPubMed

43.

Zhao H, Orhan YC, Zha X, Esencan E, Chatterton RT, Bulun SE (2017) AMP-activated protein kinase and energy balance in breast cancer. Am J Transl Res 9(2):197–213PubMedPubMedCentral

44.

Ferrante AW Jr (2007) Obesity-induced inflammation: a metabolic dialogue in the language of inflammation. J Intern Med 262(4):408–414CrossRefPubMed

45.

Zeyda M, Stulnig TM (2009) Obesity, inflammation, and insulin resistance—a mini-review. Gerontology 55(4):379–386. https://doi.org/10.1159/000212758 CrossRefPubMed

46.

Hsieh PS, Lu KC, Chiang CF, Chen CH (2010) Suppressive effect of COX2 inhibitor on the progression of adipose inflammation in high-fat-induced obese rats. Eur J Clin Investig 40(2):164–171. https://doi.org/10.1111/j.1365-2362.2009.02239.x CrossRef

47.

Bulun SE, Lin Z, Imir G, Amin S, Demura M, Yilmaz B et al (2005) Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev 57(3):359–383CrossRefPubMed

48.

Ristimaki A, Sivula A, Lundin J, Lundin M, Salminen T, Haglund C et al (2002) Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res 62(3):632–635PubMed

49.

Bulun SE, Chen D, Moy I, Brooks DC, Zhao H (2012) Aromatase, breast cancer and obesity: a complex interaction. Trends Endocrinol Metab 23(2):83–89CrossRefPubMed

50.

Brown KA, Simpson ER (2010) Obesity and breast cancer: progress to understanding the relationship. Cancer Res 70(1):4–7CrossRefPubMed

51.

Hull MA, Ko SC, Hawcroft G (2004) Prostaglandin EP receptors: targets for treatment and prevention of colorectal cancer? Mol Cancer Ther 3(8):1031–1039PubMed

52.

Chen D, Reierstad S, Lu M, Lin Z, Ishikawa H, Bulun SE (2009) Regulation of breast cancer-associated aromatase promoters. Cancer Lett 273(1):15–27CrossRefPubMed

Title: Adiposity Results in Metabolic and Inflammation Differences in Premenopausal and Postmenopausal Women Consistent with the Difference in Breast Cancer Risk
Authors: H. Zhao
J. Wang
D. Fang
O. Lee
R. T. Chatterton
V. Stearns
S. A. Khan
S. E. Bulun
Publication date: 01-08-2018
Publisher: Springer US
Published in: Discover Oncology / Issue 4/2018
Print ISSN: 1868-8497
Electronic ISSN: 2730-6011
DOI: https://doi.org/10.1007/s12672-018-0329-6

ACC 2024 Congress Coverage

Heart Failure Video

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Adiposity Results in Metabolic and Inflammation Differences in Premenopausal and Postmenopausal Women Consistent with the Difference in Breast Cancer Risk

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2018

The Influence of Menopausal Hormone Therapy and Potential Lifestyle Interactions in Female Cancer Development—a Population-Based Prospective Study

The Flavonoid Apigenin Is a Progesterone Receptor Modulator with In Vivo Activity in the Uterus

The Impact of Hormonal Contraceptives on Breast Cancer Pathology

Androgen Receptor and Ki67 Expression and Survival Outcomes in Non-small Cell Lung Cancer

The Impact of ESR1 Mutations on the Treatment of Metastatic Breast Cancer

Risk Analysis of Prostate Cancer Treatments in Promoting Metabolic Syndrome Development and the Influence of Increased Metabolic Syndrome on Prostate Cancer Therapeutic Outcome

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page