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Adipocyte and Cell Biology

Associations between markers of mammary adipose tissue dysfunction and breast cancer prognostic factors

International Journal of Obesity volume 45, pages 195–205 (2021)Cite this article

Subjects

Abstract

Background

Obesity fosters worse clinical outcomes in both premenopausal and postmenopausal women with breast cancer. Emerging evidence suggests that an android body fat distribution in particular is deleterious for breast cancer prognosis. The extent of adipose tissue dysfunction, especially how it relates to breast cancer prognostic factors and anthropometric measurements, has not been fully investigated.

Objective

Our objective was to examine if markers of adipose tissue dysfunction, such as hypertrophy and macrophage accumulation, are relevant for the pathophysiology of breast cancer and its associated prognostic factors in a well-characterised cohort of women with breast cancer who did not receive treatment before surgery.

Methods

A consecutive series of 164 women with breast cancer provided breast adipose tissue sample. Multivariate generalised linear models were used to test associations of anthropometric indices and prognostic factors with markers of adipose tissue dysfunction.

Results

We found associations of breast adipocyte size and macrophage infiltration (number of CD68+ cells/100 adipocytes) with adiposity, particularly a strong association between breast adipocyte size and central obesity, independent of total adiposity, age and menopausal status (βadj = 0.87; p = 0.0001). We also identified relationships of adipocyte hypertrophy and macrophage infiltration with prognostic factors, such as cancer stage and tumour grade (p < 0.05). RNA expression of pro-inflammatory cytokines (IL6, TNF) and leptin was also increased as a function of adipocyte size and CD86+/CD11c+ macrophage number/100 adipocytes (p < 0.05).

Conclusions

Our findings support the model of dysfunctional adipose tissue in obesity-associated breast cancer.

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Fig. 1: Breast adipocyte size and macrophage infiltration in relation to prognostic factors and fibrosis.

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References

  1. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:1625–38.

    Article  Google Scholar 

  2. Widschwendter P, Friedl TW, Schwentner L, DeGregorio N, Jaeger B, Schramm A, et al. The influence of obesity on survival in early, high-risk breast cancer: results from the randomized SUCCESS A trial. Breast Cancer Res. 2015;17:129.

    Article  Google Scholar 

  3. Cho WK, Choi DH, Park W, Cha H, Nam SJ, Kim SW, et al. Effect of body mass index on survival in breast cancer patients according to subtype, metabolic syndrome, and treatment. Clin Breast Cancer. 2018;18:e1141–7.

    Article  Google Scholar 

  4. Biganzoli E, Desmedt C, Fornili M, de Azambuja E, Cornez N, Ries F, et al. Recurrence dynamics of breast cancer according to baseline body mass index. Eur J Cancer. 2017;87:10–20.

    Article  Google Scholar 

  5. Copson ER, Cutress RI, Maishman T, Eccles BK, Gerty S, Stanton L, et al. Obesity and the outcome of young breast cancer patients in the UK: the POSH study. Ann Oncol. 2015;26:101–12.

    Article  CAS  Google Scholar 

  6. Tchernof A, Després JP. Pathophysiology of human visceral obesity: an update. Physiol Rev. 2013;93:359–404.

    Article  CAS  Google Scholar 

  7. George SM, Bernstein L, Smith AW, Neuhouser ML, Baumgartner KB, Baumgartner RN, et al. Central adiposity after breast cancer diagnosis is related to mortality in the Health, Eating, Activity, and Lifestyle study. Breast Cancer Res Treat. 2014;146:647–55.

    Article  Google Scholar 

  8. Abrahamson PE, Gammon MD, Lund MJ, Flagg EW, Porter PL, Stevens J, et al. General and abdominal obesity and survival among young women with breast cancer. Cancer Epidemiol Biomarkers Prev. 2006;15:1871–7.

    Article  Google Scholar 

  9. Russo L, Lumeng CN. Properties and functions of adipose tissue macrophages in obesity. Immunology. 2018;155:407–17.

    Article  CAS  Google Scholar 

  10. Laforest S, Labrecque J, Michaud A, Cianflone K, Tchernof A. Adipocyte size as a determinant of metabolic disease and adipose tissue dysfunction. Crit Rev Clin Lab Sci. 2015;52:301–13.

    Article  CAS  Google Scholar 

  11. Blüher M. Adipose tissue dysfunction in obesity. Exp Clin Endocrinol Diabetes. 2009;117:241–50.

    Article  Google Scholar 

  12. Michaud A, Tordjman J, Pelletier M, Liu Y, Laforest S, Noël S, et al. Relevance of omental pericellular adipose tissue collagen in the pathophysiology of human abdominal obesity and related cardiometabolic risk. Int J Obes. 2016;40:1823–31.

    Article  CAS  Google Scholar 

  13. Divoux A, Tordjman J, Lacasa D, Veyrie N, Hugol D, Aissat A, et al. Fibrosis in human adipose tissue: composition, distribution, and link with lipid metabolism and fat mass loss. Diabetes. 2010;59:2817–25.

    Article  CAS  Google Scholar 

  14. Morris PG, Hudis CA, Giri D, Morrow M, Falcone DJ, Zhou XK, et al. Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer. Cancer Prev Res. 2011;4:1021–9.

    Article  CAS  Google Scholar 

  15. 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;8:349–58.

    Article  CAS  Google Scholar 

  16. Hanna M, Dumas I, Jacob S, Têtu B, Diorio C. Physical activity, mammographic density, and age-related lobular involution among premenopausal and postmenopausal women. Menopause. 2015;22:964–75.

    Article  Google Scholar 

  17. Laforest S, Pelletier M, Michaud A, Daris M, Descamps J, Soulet D, et al. Histomorphometric analyses of human adipose tissues using intact, flash-frozen samples. Histochem Cell Biol. 2018;149:209–18.

    Article  CAS  Google Scholar 

  18. Ghosh K, Vachon CM, Pankratz VS, Vierkant RA, Anderson SS, Brandt KR, et al. Independent association of lobular involution and mammographic breast density with breast cancer risk. J Natl Cancer Inst. 2010;102:1716–23.

    Article  Google Scholar 

  19. Brown KA, Iyengar NM, Zhou XK, Gucalp A, Subbaramaiah K, Wang H, et al. Menopause is a determinant of breast aromatase expression and its associations with BMI, inflammation, and systemic markers. J Clin Endocrinol Metab. 2017;102:1692–701.

    Article  Google Scholar 

  20. Vaysse C, Lomo J, Garred O, Fjeldheim F, Lofteroed T, Schlichting E, et al. Inflammation of mammary adipose tissue occurs in overweight and obese patients exhibiting early-stage breast cancer. NPJ Breast Cancer. 2017;3:19.

    Article  Google Scholar 

  21. Pouliot MC, Després JP, Lemieux S, Moorjani S, Bouchard C, Tremblay A, et al. Waist circumference and abdominal sagittal diameter: best simple anthropometric indexes of abdominal visceral adipose tissue accumulation and related cardiovascular risk in men and women. Am J Cardiol. 1994;73:460–8.

    Article  CAS  Google Scholar 

  22. 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;22:2283–9.

    Article  CAS  Google Scholar 

  23. Hanna M, Dumas I, Orain M, Jacob S, Têtu B, Diorio C. Association between physical activity and the expression of mediators of inflammation in normal breast tissue among premenopausal and postmenopausal women. Cytokine. 2018;102:151–60.

    Article  CAS  Google Scholar 

  24. Harwani SC. Macrophages under pressure: the role of macrophage polarization in hypertension. Transl Res. 2018;191:45–63.

    Article  CAS  Google Scholar 

  25. Veilleux A, Rhéaume C, Daris M, Luu-The V, Tchernof A. Omental adipose tissue type 1 11 beta-hydroxysteroid dehydrogenase oxoreductase activity, body fat distribution, and metabolic alterations in women. J Clin Endocrinol Metab. 2009;94:3550–7.

    Article  CAS  Google Scholar 

  26. Veilleux A, Laberge PY, Morency J, Noël S, Luu-The V, Tchernof A. Expression of genes related to glucocorticoid action in human subcutaneous and omental adipose tissue. J Steroid Biochem Mol Biol. 2010;122:28–34.

    Article  CAS  Google Scholar 

  27. Laforest S, Pelletier M, Denver N, Poirier B, Nguyen S, Walker BR, et al. Simultaneous quantification of estrogens and glucocorticoids in human adipose tissue by liquid-chromatography-tandem mass spectrometry. J Steroid Biochem Mol Biol. 2019;195:105476.

    Article  Google Scholar 

  28. Springer NL, Iyengar NM, Bareja R, Verma A, Jochelson MS, Giri DD, et al. Obesity-associated extracellular matrix remodeling promotes a macrophage phenotype similar to tumor-associated macrophages. Am J Pathol. 2019;189:2019–35.

    Article  CAS  Google Scholar 

  29. Lackey DE, Burk DH, Ali MR, Mostaedi R, Smith WH, Park J, et al. Contributions of adipose tissue architectural and tensile properties toward defining healthy and unhealthy obesity. Am J Physiol Endocrinol Metab. 2014;306:E233–46.

    Article  CAS  Google Scholar 

  30. 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. 2017;10:235–43.

    Article  CAS  Google Scholar 

  31. Michaud A, Drolet R, Noël S, Paris G, Tchernof A. Visceral fat accumulation is an indicator of adipose tissue macrophage infiltration in women. Metabolism. 2012;61:689–98.

    Article  CAS  Google Scholar 

  32. Sanchez-Navarro I, Gamez-Pozo A, Gonzalez-Baron M, Pinto-Marin A, Hardisson D, Lopez R, et al. Comparison of gene expression profiling by reverse transcription quantitative PCR between fresh frozen and formalin-fixed, paraffin-embedded breast cancer tissues. Biotechniques. 2010;48:389–97.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank all research team members who were involved in data acquisition and patient’s recruitment, including Lucie Tellier, Isabelle Dumas and Karine Plourde. We express gratitude to all the participants for allowing access to their biological samples and data, and for the time they devoted to answer questionnaires. This work was supported by an Intercenter Structuring Initiative of the Cardiometabolic health, Diabetes and Obesity (CMDO) Research Network to CD, AT and FD, and grants to CD from the Canadian Breast Cancer Research Alliance (#20462), the Fondation du cancer du sein du Québec and the Banque de tissus et données of the Réseau de recherche sur le cancer of the Fonds de recherche du Québec-santé (FRQS) associated with the Canadian Tumour Repository Network (CTRNet). SL is the recipient of Ph.D. scholarships from the FRQS and the Canadian Institutes of Health Research (CIHR) (GSD 154162). CD holds an Investigator Awards (Senior) from the FRQS.

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Authors and Affiliations

  1. CHU de Québec-Université Laval Research Center (Endocrinology and Nephrology Division), School of Nutrition, Faculty of Agriculture and Food Sciences, Université Laval, Quebec City, QC, Canada

    Sofia Laforest & André Tchernof

  2. Quebec Heart Lung Institute, Quebec City, QC, Canada

    Sofia Laforest, Marie-Frédérique Gauthier & André Tchernof

  3. CHU de Québec-Université Laval Research Center (Oncology Division), Université Laval Cancer Research Center and Department of Social and Preventive Medicine, Faculty of Medicine, Université Laval, Quebec City, QC, Canada

    Kaoutar Ennour-Idrissi, Annick Michaud & Caroline Diorio

  4. CHU de Québec-Université Laval Research Center (Endocrinology and Nephrology Division), Université Laval Cancer Research Center and Department of Molecular Medicine, Faculty of Medicine, Université Laval, Quebec City, QC, Canada

    Geneviève Ouellette & Francine Durocher

  5. Centre des Maladies du Sein, Hôpital Saint-Sacrement, Quebec City, QC, Canada

    Caroline Diorio

Authors
  1. Sofia Laforest
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  2. Kaoutar Ennour-Idrissi
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  8. Caroline Diorio
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Contributions

SL designed research study; conducted experiments; acquired, analysed and interpreted data; wrote the paper; critically revised the paper; and gave final approval. KEI provided pathologic examination of tissue specimens; contributed to acquire data and interpreted data; critically revised the paper; and gave final approval. GO conducted experiments; critically revised the paper; and gave final approval. MFG conducted experiments; contributed to acquire data; critically revised the paper; and gave final approval. AM provided biological specimens and experimental protocols; critically revised the paper; and gave final approval. FD funded the study and gave final approval. AT funded and designed the study; interpreted data; critically revised the paper; gave final approval; and supervised the study. CD funded and designed the study; acquired, analysed and interpreted data; critically revised the paper; gave final approval; and supervised the study.

Corresponding author

Correspondence to Caroline Diorio.

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Conflict of interest

AT is the recipient of research grant support from Johnson & Johnson Medical Companies and Medtronic for studies unrelated to this publication. He has received consulting fees from Bausch Health. The remaining authors have no potential conflicts of interest to declare.

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Laforest, S., Ennour-Idrissi, K., Ouellette, G. et al. Associations between markers of mammary adipose tissue dysfunction and breast cancer prognostic factors. Int J Obes 45, 195–205 (2021). https://doi.org/10.1038/s41366-020-00676-3

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