Inflammation and Increased Aromatase Expression Occur in the Breast Tissue of Obese Women with Breast Cancer

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Cancer Prevention Research (Impact Factor: 4.44). 06/2011; 4(7):1021-9. DOI: 10.1158/1940-6207.CAPR-11-0110
Source: PubMed


Obesity is a risk factor for the development of hormone receptor-positive breast cancer in postmenopausal women and has been associated with an increased risk of recurrence and reduced survival. In humans, obesity causes subclinical inflammation in visceral and subcutaneous adipose tissue, characterized by necrotic adipocytes surrounded by macrophages forming crown-like structures (CLS). Recently, we found increased numbers of CLS, activation of the NF-κB transcription factor, and elevated aromatase levels and activity in the mammary glands of obese mice. These preclinical findings raised the possibility that the obesity → inflammation axis is important for the development and progression of breast cancer. Here, our main objective was to determine if the findings in mouse models of obesity translated to women. Breast tissue was obtained from 30 women who underwent breast surgery. CLS of the breast (CLS-B) was found in nearly 50% (14 of 30) of patient samples. The severity of breast inflammation, defined as the CLS-B index, correlated with both body mass index (P < 0.001) and adipocyte size (P = 0.01). Increased NF-κB binding activity and elevated aromatase expression and activity were found in the inflamed breast tissue of overweight and obese women. Collectively, our results suggest that the obesity → inflammation → aromatase axis is present in the breast tissue of most overweight and obese women. The presence of CLS-B may be a biomarker of increased breast cancer risk or poor prognosis.

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Available from: Kotha Subbaramaiah, May 13, 2014
    • "Androgens such as T are known to play a significant role in obesity, glucose homeostasis, and lipid metabolism (Saad and Gooren, 2011). Obesity and metabolic diseases have been shown to increase the incidence of breast cancer (Eliassen et al., 2006), increase aromatase expression in breast tissue (Morris et al., 2011), worsen the outcome of hormone-receptor-positive breast cancer (Sparano et al., 2010), and reduce responsiveness to endocrine therapy (Pfeiler et al., 2011). Also, it has been reported that obesity promotes breast cancer by modifying insulin and the insulin-like growth factor (IGF) axis and by changing circulating levels of cytokines and adipokines (Roberts et al., 2010). "
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    ABSTRACT: Multiple mechanisms exist for endocrine disruption; one non-receptor mediated mechanism is via effects on aromatase, an enzyme critical for maintaining the normal in vivo balance of androgens and estrogens. We adapted the AroER tri-screen 96-well assay to 1536-well format to identify potential aromatase inhibitors (AIs) in the U.S. Tox21 10K compound library. In this assay, screening with compound alone identifies estrogen receptor alpha (ERα) agonists, screening in the presence of testosterone (T) identifies AIs and/or ERα antagonists, and screening in the presence of 17β-estradiol (E2) identifies ERα antagonists. Screening the Tox-21 library in the presence of T resulted in finding 302 potential AIs. These compounds, along with 31 known AI actives and inactives, were rescreened using all three assay formats. Of the 333 compounds tested, 113 (34%; 63 actives, 50 marginal actives) were considered to be potential AIs independent of cytotoxicity and ER antagonism activity. Structure-activity analysis suggested the presence of both conventional (e.g., 1, 2, 4, - triazole class) and novel AI structures. Due to their novel structures, fourteen of the 63 potential AI actives, including both drugs and fungicides, were selected for confirmation in the biochemical tritiated water-release aromatase assay. Ten compounds were active in the assay; the remaining four were only active in high-throughput screen assay, but with low efficacy. To further characterize these 10 novel AIs, we investigated their binding characteristics. The AroER tri-screen, in high-throughput format, accurately and efficiently identified chemicals in a large and diverse chemical library that selectively interact with aromatase. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email:
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    • "Increase in WAT mass, thus, leads into increased peripheral conversion of androgens to estrogens . Moreover, obesity-associated inflammatory factors upregulate aromatase gene expression in WAT of women (Morris et al., 2011; Subbaramaiah et al., 2012), indicating that low-grade inflammation further contributes to increased estrogen biosynthesis in WAT of obese individuals. Very little, however, is known about the regulation of CYP19A1 gene expression, or the effects of locally produced estrogens in male WAT. "
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    ABSTRACT: Obesity and white adipose tissue (WAT) inflammation are associated with enhanced aromatization in women, but little is known about the regulation of aromatase (CYP19A1) gene expression in male WAT. We investigated the impact of weight gain and WAT inflammation on the regulation of CYP19A1 in males, by utilizing the hARO-Luc aromatase reporter mouse model containing a >100-kb 5'-region of the human CYP19A1 gene. We show that hARO-Luc reporter activity is enhanced in WAT of mice with increased adiposity and inflammation. Dexamethasone and TNFα, as well as forskolin and phorbol 12-myristate 13-acetate upregulate hARO-Luc activity, suggesting the involvement of promoters I.4 and I.3/II. Furthermore, we show that diet enriched with antioxidative plant polyphenols, attenuate WAT inflammation and hARO-Luc activity in obese males. In conclusion, our data suggest that obesity-associated WAT inflammation leads to increased peripheral CYP19A1 expression in males, and that polyphenol-enriched diet may have the potential to attenuate excessive aromatization in WAT of obese men. Copyright © 2015. Published by Elsevier Ireland Ltd.
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    • "In this exploratory study we aimed to ascertain whether salivary methylation of the CYP19A1 and PPARG promoters was related to age at breast or pubic hair development in girls, both independently and in concert with body size. In light of the current literature, we anticipated overweight girls with CYP19A1 hypomethylation and PPARG hypermethylation might be predisposed to early breast development [33-35], and those with PPARG hypermethylation to early pubic hair development [9,16]. "
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