Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers

Context Most estrogen-dependent breast cancers occur after menopause, despite low levels of circulating estrogens. Breast expression of the estrogen-biosynthetic enzyme, aromatase, is proposed to drive breast cancer development after menopause. However, the effects of menopause on breast aromatase expression are unknown. Objective To determine the effect of menopause on breast aromatase expression in relation to body mass index (BMI), white adipose tissue inflammation (WATi), and systemic markers of metabolic dysfunction. Design, Setting, and Participants Cross-sectional study of 102 premenopausal (age 27 to 56) and 59 postmenopausal (age 45 to 74) women who underwent mastectomy for breast cancer treatment/prevention. Outcome Breast tissue was assessed for the presence of crown-like structures and the expression and activity of aromatase. Systemic markers examined include interleukin (IL)-6, insulin, glucose, leptin, adiponectin, high-sensitivity C-reactive protein (hsCRP), cholesterol, and triglycerides. Multivariable analysis was performed for aromatase messenger RNA (mRNA) in relation to BMI, WATi, and blood markers. Results Postmenopausal women had higher BMI and more breast WATi than premenopausal women. Fasting levels of IL-6, glucose, leptin, hsCRP, and homeostatic model assessment 2 insulin resistance score were higher in the postmenopausal group. BMI was positively correlated with aromatase mRNA in both pre- and postmenopausal women. Aromatase levels were higher in breast tissue of postmenopausal women, with levels being higher in inflamed vs noninflamed, independent of BMI. Adipocyte diameter and levels of leptin, hsCRP, adiponectin, and high-density lipoprotein cholesterol were more strongly correlated with aromatase in postmenopausal than premenopausal women. Conclusions Elevated aromatase in the setting of adipose dysfunction provides a possible mechanism for the higher incidence of hormone-dependent breast cancer in obese women after menopause.

[1]  Gretchen L. Gierach,et al.  Relationship between crown-like structures and sex-steroid hormones in breast adipose tissue and serum among postmenopausal breast cancer patients , 2017, Breast Cancer Research.

[2]  O. Franco,et al.  Association of Age at Onset of Menopause and Time Since Onset of Menopause With Cardiovascular Outcomes, Intermediate Vascular Traits, and All-Cause Mortality: A Systematic Review and Meta-analysis. , 2016, JAMA cardiology.

[3]  Catherine Kim,et al.  Association of Mid-Life Changes in Body Size, Body Composition and Obesity Status with the Menopausal Transition , 2016, Healthcare.

[4]  C. Hudis,et al.  Systemic Correlates of White Adipose Tissue Inflammation in Early-Stage Breast Cancer , 2015, Clinical Cancer Research.

[5]  E. Simpson,et al.  Aromatase overexpression in dysfunctional adipose tissue links obesity to postmenopausal breast cancer , 2015, The Journal of Steroid Biochemistry and Molecular Biology.

[6]  M. Sherman,et al.  Relationships of sex steroid hormone levels in benign and cancerous breast tissue and blood: A critical appraisal of current science , 2015, Steroids.

[7]  C. Hudis,et al.  Menopause Is a Determinant of Breast Adipose Inflammation , 2015, Cancer Prevention Research.

[8]  H. Sasano,et al.  Prostaglandin E2 inhibits p53 in human breast adipose stromal cells: a novel mechanism for the regulation of aromatase in obesity and breast cancer. , 2015, Cancer research.

[9]  R. Burger,et al.  American Society of Clinical Oncology position statement on obesity and cancer. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  B. Ljung,et al.  Breast cancer version 3.2014. , 2014, Journal of the National Comprehensive Cancer Network : JNCCN.

[11]  V. Henderson,et al.  Cognition, mood, and physiological concentrations of sex hormones in the early and late postmenopause , 2013, Proceedings of the National Academy of Sciences.

[12]  P. Chedraui,et al.  Understanding weight gain at menopause , 2012, Climacteric : the journal of the International Menopause Society.

[13]  K. Matthews,et al.  Body Mass Index Following Natural Menopause and Hysterectomy with and without Bilateral Oophorectomy , 2012, International Journal of Obesity.

[14]  J. Lavoie,et al.  The effect of the menopausal transition on body composition and cardiometabolic risk factors: a Montreal-Ottawa New Emerging Team group study , 2012, Menopause.

[15]  C. Hudis,et al.  Inflammation and Increased Aromatase Expression Occur in the Breast Tissue of Obese Women with Breast Cancer , 2011, Cancer Prevention Research.

[16]  Priya Bhardwaj,et al.  Obesity Is Associated with Inflammation and Elevated Aromatase Expression in the Mouse Mammary Gland , 2011, Cancer Prevention Research.

[17]  K. Matthews,et al.  American Journal of Epidemiology Original Contribution Reproductive Hormones and Obesity: 9 Years of Observation from the Study of Women's Health across the Nation , 2022 .

[18]  A. Esteghamati,et al.  Menopause is an independent predictor of metabolic syndrome in Iranian women. , 2010, Maturitas.

[19]  T. Aas,et al.  Tissue estradiol is selectively elevated in receptor positive breast cancers while tumour estrone is reduced independent of receptor status , 2009, The Journal of Steroid Biochemistry and Molecular Biology.

[20]  E. Simpson,et al.  Subcellular localization of cyclic AMP-responsive element binding protein-regulated transcription coactivator 2 provides a link between obesity and breast cancer in postmenopausal women. , 2009, Cancer research.

[21]  N. Woods,et al.  Adipokines, inflammation, and visceral adiposity across the menopausal transition: a prospective study. , 2009, The Journal of clinical endocrinology and metabolism.

[22]  V. Somers,et al.  Accuracy of body mass index in diagnosing obesity in the adult general population , 2008, International Journal of Obesity.

[23]  Bingshu E. Chen,et al.  Breast cancer mortality trends in the United States according to estrogen receptor status and age at diagnosis. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  M. Yosef,et al.  Changes in body composition in women over six years at midlife: ovarian and chronological aging. , 2007, The Journal of clinical endocrinology and metabolism.

[25]  Shupei Wang,et al.  Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans Published, JLR Papers in Press, September 8, 2005. DOI 10.1194/jlr.M500294-JLR200 , 2005, Journal of Lipid Research.

[26]  Y. Murata,et al.  Adipose aromatase gene expression is greater in older women and is unaffected by postmenopausal estrogen therapy , 2005, Menopause.

[27]  M. C. Carr,et al.  The emergence of the metabolic syndrome with menopause. , 2003, The Journal of clinical endocrinology and metabolism.

[28]  L. Houtkooper,et al.  Assessing the validity of body mass index standards in early postmenopausal women. , 2002, Obesity research.

[29]  S. Wilczynski,et al.  Aromatase gene expression and its exon I usage in human breast tumors. Detection of aromatase messenger RNA by reverse transcription-polymerase chain reaction , 1996, The Journal of Steroid Biochemistry and Molecular Biology.

[30]  N. Harada,et al.  Presence of alternatively spliced transcripts of aromatase gene in human breast cancer. , 1996, The Journal of clinical endocrinology and metabolism.

[31]  G. Chetrite,et al.  Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients. , 1996, The Journal of clinical endocrinology and metabolism.

[32]  N. Harada,et al.  Immunolocalization of aromatase and other steroidogenic enzymes in human breast disorders. , 1994, Human pathology.

[33]  S. Bulun,et al.  A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. , 1993, The Journal of clinical endocrinology and metabolism.

[34]  N. Harada,et al.  Tissue-specific expression of the human aromatase cytochrome P-450 gene by alternative use of multiple exons 1 and promoters, and switching of tissue-specific exons 1 in carcinogenesis. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[35]  H. Hauner,et al.  Tumor necrosis factor-alpha prevents the differentiation of human adipocyte precursor cells and causes delipidation of newly developed fat cells. , 1993, The Journal of clinical endocrinology and metabolism.

[36]  K. Matthews,et al.  Weight gain at the time of menopause. , 1991, Archives of internal medicine.

[37]  J. Larrick,et al.  Modulation of adipocyte differentiation by tumor necrosis factor and transforming growth factor beta , 1989, The Journal of cell biology.

[38]  R. Elton,et al.  Aromatase activity in adipose tissue from breast quadrants: a link with tumour site , 1988, British medical journal.

[39]  C. Mendelson,et al.  Regulation of aromatase activity of stromal cells derived from human adipose tissue. , 1982, Endocrinology.

[40]  D. Rabe,et al.  New aromatase assay and its application for inhibitory studies of aminoglutethimide on microsomes of human term placenta. , 1982, Journal of steroid biochemistry.

[41]  C. Mendelson,et al.  Estrogen formation in stromal cells of adipose tissue of women: induction by glucocorticosteroids. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[42]  A. Stefańska,et al.  Metabolic Syndrome and Menopause: Pathophysiology, Clinical and Diagnostic Significance. , 2015, Advances in clinical chemistry.

[43]  A. Uitterlinden,et al.  Kathleen Cuningham Foundation Consortium For Research Into Familial Breast Cancer , 2008 .

[44]  R. Martin,et al.  Tumor necrosis factor-alpha stimulates cell proliferation in adipose tissue-derived stromal-vascular cell culture: promotion of adipose tissue expansion by paracrine growth factors. , 2000, Obesity research.

[45]  C. Mendelson,et al.  Effects of aging and obesity on aromatase activity of human adipose cells. , 1985, The Journal of clinical endocrinology and metabolism.