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ECM-dependent gene expression in normal and tumor-derived mammary organoids

ABSTRACT: A critical step in metastasis is cancer cell dissemination. Dissemination and metastasis are associated with specific genetic changes and changes in extracellular matrix (ECM), but how these changes interact to enable dissemination remains unclear. Here we tested the importance of ECM to dissemination in both normal and malignant mammary epithelium. By time-lapse imaging, we observed collective invasion and dissemination directly in 3D culture. Our results reveal that the pattern of epithelial migration and local dissemination are constrained by the local ECM microenvironment. To identify RNA expression changes that could regulate these changes in cell behavior, we conducted whole genome RNA expression profiling from normal and malignant mammary epithelium in 3D culture. We collected RNA from normal and malignant epithelium during active growth at 4 days in culture in either Matrigel or collagen I. We hybridized the resulting RNA to Agilent single color microarrays with a minimum of three biologically independent microarray replicates per condition. We observed significant gene expression differences between normal and malignant epithelium, even when cultured in the same ECM. In contrast, the ECM microenvironment had a relatively small impact on RNA expression, despite its large effects on migratory strategy and local dissemination.

ORGANISM(S): Mus musculus

PROVIDER: GSE39173 | GEO | 2012/08/16

SECONDARY ACCESSION(S): PRJNA170139

REPOSITORIES: GEO

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Project description:We are using ACI and BN rats, which differ markedly in their susceptibility to 17beta-Estradiol (E2)-induced mammary cancer, to identify genetic variants and environmental factors that determine mammary cancer susceptibility. The objective of this study was to characterize the cellular and molecular responses to E2 in the mammary glands of ACI and BN rats to identify qualitative and quantitative phenotypes that associate with and/or may confer differences in susceptibility to mammary cancer. Female ACI and BN rats were treated with E2 for 1, 3 or 12 weeks and cell proliferation, apoptosis, differentiation and gene expression were evaluated. The luminal epithelium of ACI rats exhibited a rapid and sustained proliferative response to E2. By contrast, the proliferative response exhibited by the mammary epithelium of BN rats was restrained and transitory. Moreover, the epithelium of BN rats appeared to undergo differentiation in response to E2, as evidenced by production of milk proteins as well as luminal ectasia and associated changes in the extracellular matrix (ECM). Marked differences in expression of genes that encode proteins with well-defined roles in mammary gland development (Pgr, Wnt4, Tnfsf11, Prlr, Stat5a, Areg, Gata3), differentiation and milk production (Lcn2, Spp1), regulation of extracellular environment (Mmp7, Mmp9), and cell-cell or cell-ECM interactions (Cd44, Cd24, Cd52) were observed. We propose that these cellular and molecular phenotypes are heritable and may underlie, at least in part, the differences in mammary cancer susceptibility exhibited by ACI and BN rats. Two groups of 17beta-estradiol treated female rats were compared. Five ACI and five BN rats were treated with 17beta-estradiol for 12 weeks. Total RNA was isolated from the mammary glands of these animals, labeled, and hybridized to Affymetrix Rat Genome 230 2.0 Arrays (Affymetrix Inc.). Significantly differentially expressed genes were found between these groups.

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ECM-dependent gene expression in normal and tumor-derived mammary organoids

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