Molecular mechanisms linking high body mass index to breast cancer etiology in post-menopausal breast tumor and tumor-adjacent tissues

Abstract

Purpose: In postmenopausal women, high body mass index (BMI) is an established breast cancer risk factor and is associated with worse breast cancer prognosis. We assessed the associations between BMI and gene expression of both breast tumor and adjacent tissue in estrogen receptor positive (ER+) and negative (ER-) diseases to help elucidate the mechanisms linking obesity with breast cancer biology in 519 postmenopausal women from the Nurses' Health Study (NHS) and NHSII.Methods: Differential gene expression was analyzed separately in ER+ and ER-disease both comparing overweight (BMI ≥25 to <30) or obese (BMI ≥30) women to women with normal BMI (BMI <25), and per 5 kg/m 2 increase in BMI. Analyses controlled for age and year of diagnosis, physical activity, alcohol consumption and hormone therapy use. Gene set enrichment analyses were performed and validated among a subset of postmenopausal cases in The Cancer Genome Atlas (for tumor) and Polish Breast Cancer Study (for tumor-adjacent). Results:No gene was differentially expressed by BMI (FDR<0.05). BMI was significantly associated with increased cellular proliferation pathways, particularly in ER+ tumors, and increased inflammation pathways in ER-tumor and ER-tumor-adjacent tissues (FDR<0.05). High BMI was associated with upregulation of genes involved in epithelial mesenchymal transition in ER+ tumor-adjacent tissues. Conclusions:This study provides insights into molecular mechanisms of BMI influencing postmenopausal breast cancer biology. Tumor and tumor-adjacent tissues provide independent information about potential mechanisms.

Body fatness and mTOR pathway activation of breast cancer in the Women’s Circle of Health Study

“…Fuentes-Mattei et al 21 observed significant upregulation of AKT/mTOR genes in obese vs. normal-weight women with ER+ tumors ( N = 137). However, these findings were not replicated in a study of 519 postmenopausal women 23 . As obesity may affect both gene and protein expression in tumors, we focus on the latter because the mTOR pathway signaling is primarily through post-translational protein phosphorylation 24 , 25 .…”

Investigation of the adolescent female breast transcriptome and the impact of obesity

“…It is of interest that while studies of breast tissue from otherwise healthy OB women [51], OB women with breast cancer [49,50,59], and OB adult mice [60] have consistently demonstrated increased breast inflammation, an association between inflammation and estrogen synthesis and activity has only been observed in some studies. In a study of breast tissue from adult women (average age~36 years) undergoing reduction mammoplasty, Sun et al observed increased cytokine signaling and macrophage infiltration by differential gene expression and pathway analyses; genomic studies were bolstered by IHC studies demonstrating a greater number of CD68+ macrophage inflammatory foci (CLS) in breast tissue from OB than normal weight women.…”

“…Mullooly et al [50] also observed increased CLS in benign breast tissue collected from OB breast cancer patients, and CLS were associated with a higher ratio of estrogen to androgen precursors in blood and breast tissue, suggesting increased aromatase activity. Heng et al observed an enrichment of genes related to inflammation and to the early estrogen response pathway in a microarray study of ER+ breast tumor samples from OB compared with normal weight postmenopausal women enrolled in the Nurses' Health Study, but this finding was not replicated in two other large breast cancer cohorts [59]. Lastly, in studies of mammary tissue from OB adult mice [60], pro-inflammatory factor abundance was also strongly correlated with aromatase activity and with expression of two classical ER target genes, PR and TFF1.…”

Obesity-Altered Adipose Stem Cells Promote Radiation Resistance of Estrogen Receptor Positive Breast Cancer through Paracrine Signaling

“…Further, RT reduces the long-term risk for local recurrence [5].Beyond RT, systemic treatments such as endocrine therapy are also a mainstay in BC treatment; however, flexible guidelines and patient preferences often leave therapy choice to physicians' discretion although endocrine therapy is recommended for patients whose cancer display any level of estrogen expression [6,7]. Notably, it has been found that endocrine therapy and RT can be safely concurrently administered without danger of weakening disease control [6].Obesity has been implicated as a risk factor in RT resistance, metastasis, and overall poor prognosis in breast cancer [8][9][10]. Furthermore, moderate to severe obesity increases the likelihood of BC recurrence and BC-specific mortality [10,11].…”

“…Obesity has been implicated as a risk factor in RT resistance, metastasis, and overall poor prognosis in breast cancer [8][9][10]. Furthermore, moderate to severe obesity increases the likelihood of BC recurrence and BC-specific mortality [10,11].…”