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Obesity and extracellular matrix (ECM) density are considered independent risk and prognostic factors for breast cancer. Whether they are functionally linked is uncertain. We investigated the hypothesis that obesity enhances local myofibroblast content in mammary adipose tissue and that these stromal changes increase malignant potential by enhancing interstitial ECM stiffness. Indeed, mammary fat of both diet- and genetically induced mouse models of obesity were enriched for myofibroblasts and stiffness-promoting ECM components. These differences were related to varied adipose stromal cell (ASC) characteristics because ASCs isolated from obese mice contained more myofibroblasts and deposited denser and stiffer ECMs relative to ASCs from lean control mice. Accordingly, decellularized matrices from obese ASCs stimulated mechanosignaling and thereby the malignant potential of breast cancer cells. Finally, the clinical relevance and translational potential of our findings were supported by analysis of patient specimens and the observation that caloric restriction in a mouse model reduces myofibroblast content in mammary fat. Collectively, these findings suggest that obesity-induced interstitial fibrosis promotes breast tumorigenesis by altering mammary ECM mechanics with important potential implications for anticancer therapies., (Copyright © 2015, American Association for the Advancement of Science.)

Background: Although obesity increases risk and negatively affects survival for many malignancies, the prognostic implications in squamous cell carcinoma (SCC) of the oral tongue, a disease often associated with prediagnosis weight loss, are unknown., Methods: Patients with T1-T2 oral tongue SCC underwent curative-intent resection in this single-institution study. All patients underwent nutritional assessment prior to surgery. Body mass index (BMI) was calculated from measured height and weight and categorized as obese (≥ 30 kg/m(2) ), overweight (25-29.9 kg/m(2) ), or normal (18.5-24.9 kg/m(2) ). Clinical outcomes, including disease-specific survival, recurrence-free survival, and overall survival, were compared by BMI group using Cox regression., Results: From 2000 to 2009, 155 patients (90 men, 65 women) of median age 57 years (range, 18-86 years) were included. Baseline characteristics were similar by BMI group. Obesity was significantly associated with adverse disease-specific survival compared with normal weight in univariable (hazard ratio [HR] = 2.65, 95% confidence interval [CI] = 1.07-6.59; P = .04) and multivariable analyses (HR = 5.01; 95% CI = 1.69-14.81; P = .004). A consistent association was seen between obesity and worse recurrence-free survival (HR = 1.87; 95% CI = 0.90-3.88) and between obesity and worse overall survival (HR = 2.03; 95% CI = 0.88-4.65) though without reaching statistical significance (P = .09 and P = .10, respectively) in multivariable analyses., Conclusions: In this retrospective study, obesity was an adverse independent prognostic variable. This association may not have been previously appreciated due to confounding by multiple factors including prediagnosis weight loss., (© 2013 American Cancer Society.)

Elevated levels of COX-derived prostaglandin E2 (PGE2) occur in inflamed tissues. To evaluate the potential links between inflammation and breast cancer, levels of urinary prostaglandin E metabolite (PGE-M), a stable end metabolite of PGE2, were quantified. We enrolled 400 patients with breast cancer: controls with early breast cancer (n = 200), lung metastases (n = 100), and metastases to other sites (n = 100). Patients completed a questionnaire, provided urine, and had measurements of height and weight. Urinary PGE-M was quantified by mass spectrometry. Ever smokers with lung metastasis who had not been exposed to nonsteroidal anti-inflammatory drugs (NSAIDs) had the highest PGE-M levels. PGE-M levels were increased in association with elevated body mass index (BMI; P < 0.001), aging (P < 0.001), pack-year smoking history (P = 0.02), lung metastases (P = 0.02), and recent cytotoxic chemotherapy (P = 0.03). Conversely, use of NSAIDs, prototypic inhibitors of COX activity, was associated with reduced PGE-M levels (P < 0.001). On the basis of the current findings, PGE-M is likely to be a useful biomarker for the selection of high-risk subgroups to determine the use of interventions that aim to reduce inflammation and possibly the development and progression of breast cancer, especially in overweight and obese women.

Unlabelled: Obesity is a risk factor for hormone receptor-positive breast cancer in postmenopausal women. Estrogen synthesis is catalyzed by aromatase, which is encoded by CYP19. We previously showed that aromatase expression and activity are increased in the breast tissue of overweight and obese women in the presence of characteristic inflammatory foci [crown-like structures of the breast (CLS-B)]. In preclinical studies, proinflammatory prostaglandin E(2) (PGE(2)) is a determinant of aromatase expression. We provide evidence that cyclooxygenase (COX)-2-derived PGE(2) stimulates the cyclic AMP (cAMP) → PKA signal transduction pathway that activates CYP19 transcription, resulting in increased aromatase expression and elevated progesterone receptor levels in breast tissues from overweight and obese women. We further demonstrate that a measure of in-breast inflammation (CLS-B index) is a better correlate of these biologic end points than body mass index. The obesity → inflammation → aromatase axis is likely to contribute to the increased risk of hormone receptor-positive breast cancer and the worse prognosis of obese patients with breast cancer., Significance: We show that obesity-associated inflammatory foci in the human breast are associated with elevated COX-2 levels and activation of the PGE2 → cAMP → PKA signal transduction pathway resulting in increased aromatase expression. These findings help to explain the link among obesity, low-grade chronic inflammation, and breast cancer with important clinical implications.

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.

Obesity, a cause of subclinical inflammation, is a risk factor for the development of postmenopausal breast cancer and is associated with poorer cancer outcomes. Docosahexaenoic acid (DHA), an omega-3 fatty acid, possesses anti-inflammatory properties. We hypothesized that treatment with DHA would reduce the expression of proinflammatory genes and aromatase, the rate-limiting enzyme for estrogen biosynthesis, in benign breast tissue of overweight/obese women. A randomized, placebo-controlled, double-blind phase II study of DHA given for 12 weeks to overweight/obese women with a history of stage I-III breast cancer, DCIS/LCIS, Paget's disease, or proliferative benign breast disease was carried out. In this placebo controlled trial, the primary objective was to determine whether DHA (1,000 mg by mouth twice daily) reduced breast tissue levels of TNFα. Secondary objectives included evaluation of the effect of DHA on breast tissue levels of COX-2, IL1β, aromatase, white adipose tissue inflammation, and gene expression by RNA-seq. Red blood cell fatty acid levels were measured to assess compliance. From July 2013 to November 2015, 64 participants were randomized and treated on trial (32 women per arm). Increased levels of omega-3 fatty acids in red blood cells were detected following treatment with DHA (P < 0.001) but not placebo. Treatment with DHA did not alter levels of TNFα (P = 0.71), or other biomarkers including the transcriptome in breast samples. Treatment with DHA was overall well-tolerated. Although compliance was confirmed, we did not observe changes in the levels of prespecified biomarkers in the breast after treatment with DHA when compared with placebo. Cancer Prev Res; 11(4); 203-14. ©2018 AACRSee related editorial by Fabian and Kimler, p. 187.

Background: Obesity is associated with increased adipose tissue in the tongue. Chronic white adipose tissue (WAT) inflammation commonly occurs in the obese. We investigated whether WAT inflammation in the tongue impacts survival in patients with squamous cell carcinoma (SCC) of the oral tongue.Methods: In a retrospective cohort study, patients with T1 and T2 SCC of the oral tongue who underwent curative-intent resection were included. Tongue WAT inflammation was defined by the presence of dead or dying adipocytes surrounded by macrophages forming crown-like structures. The primary and secondary endpoints were disease-specific survival (DSS) and overall survival (OS), respectively. Subgroup analyses were carried out in patients without lymph node involvement for whom adjuvant therapies were not indicated.Results: Archived tissue was available from 125 patients. The median follow-up was 55 months (range, 3-156 months). Overall, 49 of 125 patients (39%) had tongue WAT inflammation, which was associated with higher body mass index, increased tumor thickness, and vascular invasion (P < .05). The 3-year DSS rate for patients with tongue WAT inflammation was 59% (95% confidence interval [CI], 46%-76%) versus 82% (95% CI, 73%-92%) for those without inflammation. For patients without lymph node involvement for whom adjuvant therapy was not indicated (N = 70), tongue WAT inflammation was associated with shortened DSS and OS (P < .05). When adjusted for body mass index and potential prognostic covariates, the hazard ratio for DSS and OS was 5.40 (95% CI, 1.20-24.26) and 2.97 (95% CI, 1.02-8.65), respectively.Conclusions: Tongue WAT inflammation is associated with worse DSS and OS in patients who have early stage SCC of the oral tongue. Cancer 2016;122:3794-3802. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]