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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-ß 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. reference x sample

ORGANISM(S): Homo sapiens

SUBMITTER: Melissa Troester

PROVIDER: E-GEOD-49175 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Relationship of mammographic density and gene expression: analysis of normal breast tissue surrounding breast cancer.

Sun Xuezheng X Gierach Gretchen L GL Sandhu Rupninder R Williams Tyisha T Midkiff Bentley R BR Lissowska Jolanta J Wesolowska Ewa E Boyd Norman F NF Johnson Nicole B NB Figueroa Jonine D JD Sherman Mark E ME Troester Melissa A MA

Clinical cancer research : an official journal of the American Association for Cancer Research 20130805 18

<h4>Purpose</h4>Previous studies of breast tissue gene expression have shown that the extratumoral microenvironment has substantial variability across individuals, some of which can be attributed to epidemiologic factors. To evaluate how mammographic density and breast tissue composition relate to extratumoral microenvironment gene expression, we used data on 121 patients with breast cancer from the population-based Polish Women's Breast Cancer Study.<h4>Experimental design</h4>Breast cancer cas ...[more]

PMID: 23918601

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Project description:Introduction: Over the past several years, we have been interested in understanding the mechanisms by which hormone-dependent (HD) mammary carcinomas grow in the absence of the stimulatory hormone. We have hypothesized that the stromal compartment plays a pivotal role in the acquisition of the hormone-independent (HI) phenotype by providing stimulatory factors that replace the proliferative effects of the hormone. Methods: We used DNA microarrays to compare the gene expression profiles of tumors from the MPA mouse breast cancer model, one hormone-dependent (C4-HD) and one hormone-independent (C4-HI), using whole tumor samples or laser-captured purified stromal and epithelial cells obtained from the same tumors. The expression of selected genes was validated by immunohistochemistry and immunofluorescence assays. Results: We identified 413 genes that were expressed in tumor stroma but not in epithelial cells. Eighty-five percent of these genes were upregulated, whereas the remaining 15% were downregulated in C4-HI tumors relative to their expression in the C4-HD tumor stroma. Several matrix metallopeptidases, including Mmp13, Mmp3, Mmp10 and Mmp9, were overexpressed in the C4-HI tumor microenvironment. On the other hand, 1100 genes were specifically expressed in the tumor parenchyma. Among them, the 29% were upregulated, whereas the remaining 71% were downregulated, in C4-HI relative to C4-HD tumor epithelium. Steap, Pdgfc, Runx2, Cxcl9 and Sdf2 were among the genes with high expression in the C4-HI tumor parenchyma. Interestingly, we found that Fgf2 was one of the few genes upregulated by MPA in C4-HD tumors, confirming its pivotal role in regulating tumor growth in this model. Conclusions: We demonstrate a gene expression profile that distinguishes epithelial from stromal cells in mammary tumors with different hormone dependence. Our results support the hypothesis that the tumor-associated stroma may contribute to hormone-independent tumor growth. The fact that Fgf2 was one of these few stimulatory genes is worth investigating. reference X sample

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Relationship of mammographic density and gene expression: analysis of normal breast tissue surrounding breast cancer

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Relationship of mammographic density and gene expression: analysis of normal breast tissue surrounding breast cancer.

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