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UNLABELLED: Inverse associations between natural vegetation exposure (i.e., greenness) and breast cancer risk have been reported; however, it remains unknown whether greenness affects breast tissue development or operates through other mechanisms (e.g., body mass index [BMI] or physical activity). We examined the association between greenness and mammographic density-a strong breast cancer risk factor-to determine whether greenness influences breast tissue composition independent of lifestyle factors. METHODS: Women (n = 2,318) without a history of breast cancer underwent mammographic screening at Brigham and Womens Hospital in Boston, Massachusetts, from 2006 to 2014. Normalized Difference Vegetation Index (NDVI) satellite data at 1-km2 resolution were used to estimate greenness at participants residential address 1, 3, and 5 years before mammogram. We used multivariable linear regression to estimate differences in log-transformed volumetric mammographic density measures and 95% confidence intervals (CIs) for each 0.1 unit increase in NDVI. RESULTS: Five-year annual average NDVI was not associated with percent mammographic density in premenopausal (β = -0.01; 95% CI = -0.03, 0.02; P = 0.58) and postmenopausal women (β = -0.02; 95% CI = -0.04, 0.01; P = 0.18). Results were similar for 1-year and 3-year NDVI measures and in models including potential mediators of BMI and physical activity. There were also no associations between greenness and dense volume and nondense volume. CONCLUSIONS: Greenness exposures were not associated with mammographic density. IMPACT: Prior observations of a protective association between greenness and breast cancer may not be driven by differences in breast tissue composition, as measured by mammographic density, but rather other mechanisms.

Approximately one third of cancer patients die due to complexities related to cachexia. However, the mechanisms of cachexia and the potential therapeutic interventions remain poorly studied. We observed a significant positive correlation between SIRT1 expression and muscle fiber cross-sectional area in pancreatic cancer patients. Rescuing Sirt1 expression by exogenous expression or pharmacological agents reverted cancer cell-induced myotube wasting in culture conditions and mouse models. RNA-seq and follow-up analyses showed cancer cell-mediated SIRT1 loss induced NF-κB signaling in cachectic muscles that enhanced the expression of FOXO transcription factors and NADPH oxidase 4 (Nox4), a key regulator of reactive oxygen species production. Additionally, we observed a negative correlation between NOX4 expression and skeletal muscle fiber cross-sectional area in pancreatic cancer patients. Knocking out Nox4 in skeletal muscles or pharmacological blockade of Nox4 activity abrogated tumor-induced cachexia in mice. Thus, we conclude that targeting the Sirt1-Nox4 axis in muscles is an effective therapeutic intervention for mitigating pancreatic cancer-induced cachexia.

Background: According to the stem cell hypothesis, breast carcinogenesis may be related to the breast stem cell pool size. However, little is known about associations of breast cancer risk factors, such as anthropometric measures, with the expression of stem cell markers in noncancerous breast tissue. Methods: The analysis included 414 women with biopsy-confirmed benign breast disease in the Nurses' Health Study and Nurses' Health Study II. Birthweight, weight at age 18, current weight, and current height were reported via self-administered questionnaires. IHC staining of stem cell markers (CD44, CD24, and aldehyde dehydrogenase family 1 member A1) in histopathologically normal epithelial and stromal breast tissue was quantified using an automated computational image analysis system. Linear regression was used to examine the associations of early-life and adult anthropometric measures with log-transformed stem cell marker expression, adjusting for potential confounders. Results: Birthweight [=10.0 vs. <5.5 lbs: ß (95% confidence interval) = 4.29 (1.02, 7.56); P trend = 0.001 in the stroma] and adult height [=67.0 vs. <63.0 inch: 0.86 (0.14, 1.58); P trend = 0.02 in the epithelium and stroma combined] were positively associated with CD44 expression. Childhood body fatness was inversely associated (P trend = 0.03) whereas adult height was positively associated with CD24 expression in combined stroma and epithelium (P trend = 0.03). Conclusions: Our data suggest that anthropometric measures, such as birthweight, adult height, and childhood body fatness, may be associated with the stem cell expression among women with benign breast disease. Impact: Anthropometric measures, such as birthweight, height, and childhood body fatness, may have long-term impacts on stem cell population in the breast. [ABSTRACT FROM AUTHOR]

Background: We investigated the associations of reproductive factors known to influence breast cancer risk with the expression of breast stem cell markers CD44, CD24, and ALDH1A1 in benign breast biopsy samples. Methods: We included 439 cancer-free women with biopsy-confirmed benign breast disease within the Nurses' Health Study (NHS) and NHSII. The data on reproductive and other breast cancer risk factors were obtained from biennial questionnaires. Immunohistochemistry (IHC) was performed on tissue microarrays. For each core, the IHC expression was assessed using a semi-automated platform and expressed as % of cells that stained positive for a specific marker out of the total cell count. Generalized linear regression was used to examine the associations of reproductive factors with a log-transformed expression of each marker (in epithelium and stroma), adjusted for other breast cancer risk factors. Results: In multivariate analysis, the time between menarche and age at first birth was inversely associated with CD44 in epithelium (β per 5 years = -0.38, 95% CI -0.69; -0.06). Age at first birth and the time between menarche and age at first birth were inversely associated with ALDH1A1 (stroma: β per 5 years = -0.43, 95% CI -0.76; -0.10 and β = -0.47, 95% CI -0.79; -0.15, respectively; epithelium: β = -0.15, 95% CI -0.30; -0.01 and β = -0.17, 95% CI -0.30; -0.03, respectively). Time since last pregnancy was inversely associated with stromal ALDH1A1 (β per 5 years = -0.55, 95% CI -0.98; -0.11). No associations were found for CD24. The observed associations were similar in premenopausal women. In postmenopausal women, lifetime duration of breastfeeding was inversely associated with stromal ALDH1A1 expression (β for ≥24 vs. 0 to <1 months = -2.24, 95% CI 3.96; -0.51, p-trend = 0.01). Conclusion: Early-life reproductive factors may influence CD44 and ALDH1A1 expression in benign breast tissue. [ABSTRACT FROM AUTHOR]

Background: Early-life and adult anthropometrics are associated with breast density and breast cancer risk. However, little is known about whether these factors also influence breast tissue composition beyond what is captured by breast density among women with benign breast disease (BBD). Methods: This analysis included 788 controls from a nested case-control study of breast cancer within the Nurses' Health Study BBD subcohorts. Body fatness at ages 5 and 10 years was recalled using a 9-level pictogram. Weight at age 18, current weight, and height were reported via questionnaires. A deep-learning image analysis was used to quantify the percentages of epithelial, fibrous stromal, and adipose tissue areas within BBD slides. We performed linear mixed models to estimate beta coefficients (β) and 95% confidence intervals (CI) for the relationships between anthropometrics and the log-transformed percentages of individual tissue type, adjusting for confounders. Results: Childhood body fatness (level ≥ 4.5 vs. 1), BMI at age 18 (≥23 vs. <19 kg/m2), and current adult BMI (≥30 vs. <21 kg/m2) were associated with higher proportions of adipose tissue [β (95% CI) = 0.34 (0.03, 0.65), 0.19 (-0.04-0.42), 0.40 (0.12, 0.68), respectively] and lower proportions of fibrous stromal tissue [-0.05 (-0.10, 0.002), -0.03 (-0.07, 0.003), -0.12 (-0.16, -0.07), respectively] during adulthood (all Ptrend < 0.04). BMI at age 18 was also inversely associated with epithelial tissue (Ptrend = 0.03). Adult height was not associated with any of the individual tissue types. Conclusions: Our data suggest that body fatness has long-term impacts on breast tissue composition. [ABSTRACT FROM AUTHOR]