Relationship of Mammographic Density and Gene Expression: Analysis of Normal Breast Tissue Surrounding Breast Cancer

Abstract

Purpose Previous studies of breast tissue gene expression have demonstrated that the extratumoral microenvironment has substantial variability across individuals, some of which can be attributed to epidemiologic factors. To evaluate how mammographic density (MD) and breast tissue composition relate to extratumoral microenvironment gene expression, we used data on 121 breast cancer patients from the population-based Polish Women's Breast Cancer Study. Design Breast cancer cases were classified based on a previously reported, biologically-defined extratumoral gene expression signature with two subtypes: an Active subtype, which is associated with high expression of genes related to fibrosis and wound response, and an Inactive subtype, which has high expression of cellular adhesion genes. MD of the contralateral breast was assessed using pre-treatment mammograms and a quantitative, reliable computer-assisted thresholding method. Breast tissue composition was evaluated based on digital image analysis of tissue sections. Results The Inactive extratumoral subtype was associated with significantly higher percentage mammographic density (PD) and dense area (DA) in univariate analysis (PD: p=0.001; DA: p=0.049) and in multivariable analyses adjusted for age and body mass index (PD: p=0.004; DA: p=0.049). Inactive/higher MD tissue was characterized by a significantly higher percentage of stroma and a significantly lower percentage of adipose tissue, with no significant change in epithelial content. Analysis of published gene expression signatures suggested that Inactive/higher MD tissue expressed increased estrogen response and decreased TGF-β signaling. Conclusions By linking novel molecular phenotypes with MD, our results indicate that MD reflects broad transcriptional changes, including changes in both epithelia- and stroma-derived signaling.

Breast Density and Breast Cancer Risk: Understanding of Biology and Risk

“…Numerous studies have investigated the relationship (measured within or between study subjects) between mammographic density and the amount or proportion of epithelial cells, adipose tissue, and/or stroma in breast tissue samples [4,20,[23][24][25][26][27][28][29]. Consistently, these studies report a positive association between mammographic density and the amount or proportion of stroma and/or collagen.…”

“…Consistently, these studies report a positive association between mammographic density and the amount or proportion of stroma and/or collagen. Likewise, the amount or proportion of adipose tissue has been consistently inversely associated with mammographic density [4,20,25,28,29]. The studies examining the association between mammographic density and the amount or proportion of epithelial cells (in some studies measured as ducts or lobules or glandular area rather than epithelial cells [24,26,28], or total nuclear area rather than epithelial nuclear area [23]) are somewhat mixed, although all studies report a positive association [4,20,[23][24][25]27] or no association [26,28,29].…”

“…The expression of these genes was lower in high-density tissue as compared with low-density tissue and in tissue from breast cancers compared with low-density tissue. Sun et al conducted gene expression profiling in nonmalignant tissue adjacent to tumor (<2 cm from the tumor margin) among 118 women undergoing breast cancer surgery [29]. Mammographic density was measured with Cumulus in the pre-treatment mammogram from the contralateral breast.…”

Racial differences in genome-wide methylation profiling and gene expression in breast tissues from healthy women

“…16 Several studies have reported associations between gene expression and breast cancer risk factors in both tumor and normal breast tissues. [17][18][19][20] Authors reported differences in gene expression by age, 17 body mass index, 18 parity, 19 and breast density. 20 There is less known about factors affecting gene expression in normal tissues from healthy individuals.…”

“…[17][18][19][20] Authors reported differences in gene expression by age, 17 body mass index, 18 parity, 19 and breast density. 20 There is less known about factors affecting gene expression in normal tissues from healthy individuals. In particular, little is known about associations of gene expression with race in breast tissues of women without breast cancer.…”