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: 5.27). 06/2011; 4(7):1021-9. DOI: 10.1158/1940-6207.CAPR-11-0110
Source: PubMed

ABSTRACT 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
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    • "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:
    Toxicological Sciences 07/2015; DOI:10.1093/toxsci/kfv141 · 4.48 Impact Factor
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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.
    Molecular and Cellular Endocrinology 06/2015; 412. DOI:10.1016/j.mce.2015.06.002 · 4.24 Impact Factor
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    • "Furthermore, chronic internal inflammation secondary to adiposity has been associated with the risk of PMBC (Aghamohammadzaeh and Heagerty 2012; Cowey and Hardy 2006; Perez De Heredia et al. 2012). Results from animal and translational clinical studies suggest of macrophage infiltration into mammary and subcutaneous adipocytes and formation of crown-like structures around necrotic adipocyte which in turn activates the transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and induces pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukines and cyclo-oxygenase-2 (COX-2) (Cowey and Hardy 2006; Perez De Heredia et al. 2012; Morris et al. 2011). These pro-inflammatory factors activate cytochrome P450 19 (CYP19) gene transcription yielding elevation in aromatase gene activity. "
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    ABSTRACT: Chronic internal inflammation secondary to adiposity is a risk factor for sporadic breast cancer and Post-Menopausal Breast Cancer (PMBC) is largely defined as such. Adiposity is one of the clinical criteria for the diagnosis of Metabolic Syndrome (MetS) and is a risk factor for PMBC. We examined SNPs of eight genes implicated in adiposity, inflammation and cell proliferation in a Prospective-specimen-collection, Retrospective-Blinded-Evaluation (PRoBE) design approach. A total of 180 cases and 732 age-matched controls were identified from the MyCode prospective biobank database and then linked to the Clinical Decision Information System, an enterprise-wide data warehouse, to retrieve clinico-demographic data. Samples were analyzed in a core laboratory where the personnel were masked to their status. Results from multivariate logistic regression yielded one SNP (rs2922126) in the GHSR as protective against PMBC among homozygotes for the minor allele (A/A) (OR = 0.4, 95% CI 0.18-.89, P-value = .02); homozygosity for the minor allele (C/C) of the SNP (rs889312) of the gene MAP3K1 was associated with the risk of PMBC (OR = 2.41, 95% CI 1.25-4.63 P-value = .008). Advanced age was protective against PMBC (OR = 0.98, 95% CI 0.95-0.99, P-value = .02). Family history of breast cancer (OR = 2.22, 95% CI 1.14-4.43. P = .02), HRT (OR = 3.35; 95% CI 2.15-5.21, P < .001), and MetS (OR = 14.83, 95% CI 5.63-39.08, P < .001) and interaction between HRT and MetS (OR = 39.38, 95% CI 15.71-98.70, P < .001) were associated with the risk of PMBC. We did not detected significant interactions between SNPs or between the SNPs and the clinico-demographic risk factors. Our study further confirms that MetS increases the risk of PMBC and argues in favor of reducing exposure to HRT. Our findings are another confirmation that low penetrance genes involved in the inflammatory pathway, i.e. MAP3KI gene, may have a plausible causative role in PMBC. Given the fact that genetic constitutionality of individuals cannot be changed, efforts should be focused on life style modification.
    SpringerPlus 11/2013; 2:638. DOI:10.1186/2193-1801-2-638
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