Background: Elevated body mass index (BMI) is associated with increased risk of postmenopausal breast cancer, which may be partly attributable to an inflammation-aromatase axis. Most individuals with elevated BMI harbor white adipose tissue inflammation (WATi), defined by the presence of crown-like structures in the breast (CLS-B). CLS-B are composed of a dead/dying adipocyte surrounded by CD68+ macrophages. This inflammation is associated with activation of NF-κB and elevated expression of aromatase, which could contribute to tumor development. Additionally, WATi correlates with several circulating changes, including hyperinsulinemia, which increase breast cancer risk. Although breast WATi correlates with rising BMI, it is also present in some normal BMI individuals. Beyond inherited germline syndromes, the etiology of breast cancer in individuals with normal BMI is not well understood. Here we examined the impact of breast WATi on breast aromatase expression and circulating factors in women with normal BMI. Methods: Non-tumorous breast tissue and fasting blood were collected from 72 women with BMI < 25 kg/m2 undergoing mastectomy at MSKCC. Breast inflammation was detected by the presence of CLS-B using CD68 immunohistochemistry. The primary objective was to determine if breast WATi in normal BMI individuals correlates with elevated aromatase levels in the breast, measured by qPCR, western blotting, immunofluorescence and enzyme activity. Secondary objectives included assessment of breast adipocyte size and circulating metabolic and inflammatory factors. Results: Breast inflammation was present in 39% of women. Median BMI was 23.0 (range 18.4 to 24.9) in women with breast WATi versus 21.8 (range 17.3 to 24.6) in those without inflammation (P=0.04). Aromatase mRNA expression was positively correlated with WATi (CLS-B/cm2; P=0.002). Those with severe WATi had highest aromatase mRNA levels, compared to those with no or mild WATi (P=0.005). Aromatase protein, assessed by measuring adipose stromal cell-specific immunofluorescence or western blotting, and activity were also higher in CLS-B+ cases compared to CLS-B- (P<0.001). Breast WATi correlated with larger adipocytes (P=0.01) and higher circulating levels of C-reactive protein, leptin, insulin, and triglycerides (P<0.05). Insulin resistance, characterized by the homeostasis model (HOMA2-IR), correlated with breast WATi (P=0.004). Finally, leptin, a known inducer of aromatase and driver of cancer growth, correlated with higher breast aromatase levels (P=0.02) and larger adipocytes (P<0.01). Conclusions: A metabolically unhealthy state occurs in women with inflamed breast adipose despite having a normal BMI. This subclinical inflammatory state is characterized by elevated aromatase in the breast, insulin resistance, and dysplipidemia. The presence of enlarged adipocytes in the breasts of normal BMI women with inflammation suggests a state of hyperadiposity which could not be predicted based on BMI alone. These findings indicate that normal BMI metabolic obesity may be associated with increased cancer risk. Our results suggest that objective measurements of adiposity rather than BMI may help to identify individuals at increased risk for disease. Citation Format: Iyengar NM, Brown KA, Zhou XK, Subbaramaiah K, Giri DD, Gucalp A, Howe LR, Zahid H, Bhardwaj P, Wendel NK, Falcone DJ, Morrow M, Wang H, Williams S, Pollak M, Hudis CA, Dannenberg AJ. Metabolic obesity, adipose inflammation and aromatase: Potential drivers of breast cancer risk in women with normal body mass index [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD5-05.
Background: In post-menopausal women, obesity is a risk factor for the development of BC that expresses the estrogen and progesterone receptors (ER/PR). In mouse models of obesity, we previously described crown-like structures (CLS), consisting of macrophages surrounding dead adipocytes in white adipose tissue (WAT) of the mammary gland, which were associated with increased levels of proinflammatory mediators known to be involved in carcinogenesis. We translated these findings to women (n = 30), and provided the first evidence of CLS in the human breast (CLS-B). The presence and severity of CLS-B (CLS-B index) correlated with elevated body mass index (BMI), increased adipocyte size, activation of NF-κB, and increased levels of proinflammatory mediators (TNF-α, IL-1β, COX-2 and PGE2) and aromatase. We expanded our population to prospectively validate these preliminary findings. Methods: We prospectively collected WAT from women undergoing breast and reconstructive surgery. WAT was subjected to immunohistochemistry for CD68, a macrophage marker, to detect CLS-B by light microscopy. Adipocyte diameter was measured on photomicrographs using the Canvas 11 Software. Endpoints were 1) CLS-B presence/absence and 2) CLS-B index (proportion of slides with CLS-B). Associations between CLS-B and clinicopathologic features were analyzed using logistic regression and Fisher's exact test. Results: From 04/2010-02/2012, WAT (100 mastectomy and 5 abdominal reconstructions) was obtained from 101 women; median age 49 (range 26-80). CLS-B were found in 54 (53%) patients (pts). CLS-B were seen in 9/37 (24%) normal weight pts (BMI <25), 23/39 (59%) overweight pts (BMI 25-29.9), and 22/25 (88%) obese pts (BMI ≥30). Pts with CLS-B had significantly larger average adipocyte diameter (106.5 +/- 11.5 microns) compared to those without CLS-B (91.5 +/- 16.1 microns; p<0.001). Consistently, CLS-B index correlated with BMI (p<0.001) and adipocyte size (p<0.001). Breast inflammation was seen in pts with all tumor phenotypes: CLS-B were seen in 24/41 (59%) pts with ER/PR+, HER2- tumors; 7/16 (44%) pts with HER2+ tumors; and 3/10 (30%) pts with ER/PR/HER2- tumors. A higher CLS-B index was seen in WAT from ER+ tumors, but this was not statistically significant (p = 0.08). Regular use of nonsteroidal antiinflammatory drugs was protective against CLS-B (p = 0.17 for association with CLS-B, and p = 0.04 for association with CLS-B index in multivariable analyses). Among 25 pts with bilateral breast WAT, concordant CLS-B findings (+/-) were found in 20 (80%) pts. Among pts with paired breast and abdominal WAT, concordant findings were seen in 4/5 (80%) pts. Conclusions: Findings from this prospective study, the largest reported to date, extend our previous observation that CLS-B are associated with BMI and adipocyte size. These results provide a plausible pathophysiological link between obesity and BC. Breast inflammation occurs in association with all BC phenotypes. Preliminary data suggest concordance between breasts and between abdominal and breast WAT. Hence, abdominal WAT may prove useful as a surrogate for breast WAT; biopsies of abdominal subcutaneous WAT are more easily done, which could prove useful in developing interventions to attenuate WAT inflammation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-06-03.
Background: Elevated body mass index (BMI) is associated with increased risk of estrogen receptor-positive postmenopausal breast cancer. Mechanistically, most individuals with elevated BMI have breast white adipose tissue inflammation (WATi) which confers increased breast cancer risk, particularly in those with existing benign breast disease. Individuals with WATi have elevated in-breast expression of aromatase and several systemic changes that increase breast cancer risk, including hyperinsulinemia and higher levels of C-reactive protein. However, women with normal BMI but high levels of body fat are also likely to harbor WATi and are at increased risk of postmenopausal breast cancer. The accuracy of BMI for assessing adiposity and predicting obesity-related disorders, including cancer, varies across race and ethnicity. Whether the association between BMI and WATi varies by race is unknown. Here we aimed to characterize relationships among breast WATi and clinicopathologic features in a racially diverse cohort undergoing mastectomy for breast cancer treatment. Methods: Non-tumorous breast tissue and fasting blood were collected from women undergoing mastectomy for breast cancer treatment or prevention at a single center serving a racially diverse patient population. Breast WATi was detected by the presence of crown-like structures in the breast (CLS-B), which are composed of a dead/dying adipocyte surrounded by CD68+ macrophages. Clinicopathologic data were abstracted from electronic medical records. Associations among categorical variables were examined using Fisher's exact test. Relationships between continuous variables were examined using the Spearman correlation. Results: As of May 18, 2018 62 patients have been accrued; median age 55 (range 32 to 84). Self-reported race distribution was: 36 (58%) Asian, 5 African American (8%), 20 (32%) Caucasian, and 1 (2%) unknown. Breast tissue has been analyzed for WATi in 60 cases thus far. Clinicopathologic features stratified by the presence or absence of breast WATi are presented in. Breast WAT inflammation was associated with obesity (P=0.02) and a trend to association was observed with dyslipidemia (P<0.09). VariableBreast WATi Absent (n=25)Breast WATi Present (n=35)Age, years Median (range)51 (32 to 71)59 (36 to 80)BMI, kg/m2 Median (range)22.5 (18.1 to 35.3)28.0 (19.2 to 38.9)BMI Category Underweight1 (4%)0 (0%)Normal16 (64%)10 (29%)Overweight5 (20%)18 (51%)Obese3 (12%)7 (20%)Race, n (%) Asian15 (60%)19 (54%)African American2 (8%)3 (9%)Caucasian8 (32%)12 (34%)Unknown0 (0%)1 (3%)Menopausal Status, n (%) Pre10 (40%)12 (34%)Post15 (60%)23 (66%)Hypertension, n (%)7 (28%)16 (46%)Diabetes mellitus, n (%)0 (0%)5 (14%)Dyslipidemia, n (%)1 (4%)11 (31%) Conclusions: Breast adipose inflammation is associated with elevated BMI and possibly metabolic syndrome disorders in a racially diverse population. These findings are consistent with observations from predominantly Caucasian cohorts. Race-specific characteristics will also be examined. Study accrual is ongoing and updated results will be presented. Citation Format: Iyengar NM, Siegel B, Malik M, Giri DD, Tsai J, Hughes M, Adam A, Williams S, Zhou XK, Rodgers W, Ginter P, Patel A, Yong F, Cherian A, August P, Dannenberg AJ. Obesity, adipose inflammation, and race in patients with early stage breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-05.
6614 Background: Childhood cancer survivors (CCS) have a high frequency of growth hormone deficiency (GHD) and risk of early cardiovascular disease (CVD). This study examined the relations between GHD and risk factors for CVD in CCS. Methods: Anthropometrics, blood pressure, lipids, growth hormone (GH) stimulation test, dual-energy x-ray absorptiometry, abdominal CT, and insulin resistance (IR) (euglycemic, hyperinsulinemic clamp - low M/lbm signifies IR) were obtained in 174 CCS, mean age 15±2 years and 89 healthy sibling controls, mean age 13.5±3 years. Linear regression evaluated the relations between GHD and CVD risk factors, adjusted for sex, age, pubertal stage, and body mass index (BMI) or visceral fat. Results: 62 CCS (36%) had GHD. There were no significant measurement differences between non-GHD CCS and controls. Compared to controls, GHD CCS who never received GH (N = 34) had greater BMI (24.8 vs 20.8 kg/m2, p < 0.0001), percent body fat (36.1% vs 25.8%, p < 0.0001), visceral fat (34.8 vs 19.6 cm2, p < 0.0001), and triglycerides (TG) (120.2 vs 83.8 mg/dL, p = 0.001) and were more IR (M/lbm 11.1 vs 14.2 mg/kg/min, p = 0.0006). Adjustment for BMI and visceral fat did not change the IR or TG results. GHD CCS currently on GH had lower BMI (21.9 kg/m2, p = 0.02), percent body fat (31.2%, p = 0.08), and visceral fat (26.5 cm2, p = 0.03) compared to those not treated. IR and TG were not different between treated and not treated GHD CCS. Conclusions: GHD is a common finding in CCS and is significantly associated with adiposity, IR, and elevated TG.There is a suggestion that GH treatment had a positive impact on adiposity, but not IR and TG levels. These study findings imply that CVD risk factors are present in CCS with GHD independent of body fatness, suggesting that the cancer diagnosis or treatments received may lead to early cardiovascular disease in childhood cancer survivors. No significant financial relationships to disclose.
Background: Elevated body mass index (BMI) is associated with increased risk of hormone receptor (HR)-positive breast cancer in postmenopausal women and worsened outcomes after breast cancer diagnosis. These observations may be partly attributable to adipose inflammation, which is prevalent in the breasts of obese women and is associated with worsened breast cancer survival. In men, some studies have reported obesity to be a risk factor for breast cancer, however the biologic links are not well characterized. Whether adipose inflammation occurs in male breast tissue has not been previously reported. Here we examined the relationships among pre-diagnosis BMI, adipose inflammation, and breast cancer features in men. Methods: Males diagnosed with stage 0 – III breast cancer who underwent mastectomy at Memorial Sloan Kettering (MSK) between August 1991 – November 2011 were included in this retrospective cohort study. Pre-operative BMI was categorized as normal or underweight (<25), overweight (25 – 29.9), obese (≥30), or morbidly obese (≥40 or ≥35 + co-morbidity). Archived breast tissue was subjected to CD68 immunohistochemistry to detect adipose inflammation, defined by the presence of dead or dying adipocytes surrounded by macrophages – known as crown-like structures of the breast (CLS-B). Clinicopathologic associations with BMI and CLS-B were analyzed by logistic regression and Fisher's exact test. Results: A total of 141 men were included; median age 63 (range 23 – 96). By BMI category, 25 were normal or underweight, 65 overweight, and 51 obese – of which 19 were morbidly obese. Only 11 men had known BRCA1/2 mutations. Median age at diagnosis was 69 in normal/underweight men versus 63 in obese men and 51 in morbidly obese men (P≤0.05). Among those with invasive tumors, average tumor size was 1.50 cm (± 0.84) in normal/underweight men versus 2.04 (±0.81) in morbidly obese men (P≤0.05). Archived breast tissue was available from 92 (65%) men. Breast adipose inflammation was present in 55 (60%) men, and average BMI was 31 (±8) versus 28 (±5) in men with versus without inflammation, respectively (P=0.07). Conclusions: Obesity is associated with early onset breast cancer in men. Morbidly obese men were diagnosed with breast cancer at an even younger age and had larger tumors than normal weight individuals. These findings support further studies to investigate mechanisms, such as adipose inflammation, through which obesity may promote breast cancer in men. Citation Format: Williams S, Parrish JC, Zhou XK, Wang H, Dierickx A, Gucalp A, Dannenberg AJ, Iyengar NM. Obesity and adipose inflammation in men with breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-10-04.
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