Breast adipose regulation of premenopausal breast epithelial phenotype involves interleukin 10

Abstract

Epidemiological studies inversely associate body mass index (BMI) with breast cancer risk in premenopausal women, but the pathophysiological linkage remains ill-defined. Despite the documented relevance of the ‘local’ environment to breast cancer progression and the well-accepted differences in transcriptome and metabolic properties of anatomically distinct fat depots, specific breast adipose contributions to the proliferative potential of non-diseased breast glandular compartment are not fully understood. To address early breast cancer causation in the context of obesity status, we compared the cellular and molecular phenotypes of breast adipose and matched breast glandular tissue from premenopausal non-obese (mean BMI=27 kg/m2) and obese (mean BMI=44 kg/m2) women. Breast adipose from obese women showed higher expression levels of adipogenic, pro-inflammatory and estrogen synthetic genes, than from non-obese women. Obese breast glandular tissue displayed lower proliferation and inflammatory status and higher expression of anti-proliferative/pro-senescence biomarkers TP53 and p21, than from non-obese women. Transcript levels for T-cell receptor and co-receptors CD3 and CD4 were higher in breast adipose of obese cohorts, coincident with elevated adipose Interleukin 10 (IL10) and FOXP3 gene expression. In human breast epithelial cell lines MCF10A and HMEC, recombinant human IL10 reduced cell viability and CCND1 transcript levels, increased those of TP53 and p21, and promoted (MCF10A) apoptosis. Our findings suggest that breast adipose-associated IL10 may mediate paracrine interactions between non-diseased breast adipose and breast glandular compartments and highlight how breast adipose may program the local inflammatory milieu, partly by recruiting FOXP3+ T regulatory cells, to influence premenopausal breast cancer risk.

Malic Enzyme 1 (ME1) Promotes Adiposity and Hepatic Steatosis and Induces Circulating Insulin and Leptin in Obese Female Mice

“…ME1 increased gene expression of ACACA, which is highly enriched in lipogenic tissues and constitutes the first and rate-limiting step in fatty acid biosynthesis. Given that mammary adipocytes are an important component of the tumor microenvironment in mammary cancers [ 50 ], and since leptin is considered to promote breast cancer [ 19 , 20 ], our results suggest the possible utility of targeting mammary ME1 for breast cancer treatment.…”

Association of Mammographic Density and Benign Breast Calcifications Individually or Combined with Hypertension, Diabetes, and Hypercholesterolemia in Women ≥40 Years of Age: A Retrospective Study

“…Breast adipose tissue is an endocrine organ that secretes adipokines, cytokines, chemokines, and growth factors 17. Women with increased body fat exhibit greater breast inflammation with higher levels of circulating metaboinflammatory factors,11 and greater expression of adipogenic and proinflammatory genes is detected in the breast adipose tissue of obese women compared with non-obese women 18…”

“…adipogenic and proinflammatory genes is detected in the breast adipose tissue of obese women compared with nonobese women. 18 Limited available evidence has focused on the association of MD with the metabolic syndrome cluster 10 19-23 rather than individual CVD risk factors. Inconsistencies in the results are noted, likely due to the small number of participants, 10 21 24 inclusion of variable age groups (premenopausal, 22 postmenopausal, 21 or both 19 ), and multiple ethnicities.…”

Understanding the mechanisms underlying obesity in remodeling the breast tumor immune microenvironment: from the perspective of inflammation

“…Increased adiposity caused by ovarian hormone deficiency in ovariectomized mice results in enhanced expression of aromatase in mammary adipose tissue mediated by decreased local IL-10. Similarly, Alhallak et al 44 reported that compared to normal weight women, IL-10 and FOXP3+ T regulatory levels in breast adipose tissue of obese premenopausal women were upregulated along with the expression of tumor suppressive markers in breast tissue. In vitro application of IL-10 was shown to promote apoptosis and inhibit proliferation in the mammary epithelial cell lines, MCF10A and HMEC.…”