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ATF3-induced mammary tumors exhibit molecular features of human basal-like breast cancer

ABSTRACT: Transcriptional profiling of mammary tumors that occurs in parous, BK5.ATF3 mice, compared to adjacent normal mammary tissue

ORGANISM(S): Mus musculus

PROVIDER: GSE162804 | GEO | 2021/03/23

REPOSITORIES: GEO

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BK5.ATF3-induced mammary tumors compared to normal mammary glands

Project description:Transcriptional profiling of mammary tumors that occur in parous, BK5.ATF3 mice, compared to normal mammary tissue

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BK5.ATF3-induced mammary tumors compared to normal mammary glands

Project description:BK5.ATF3-induced mammary tumors compared to normal mammary glands

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ATF3-induced mammary tumors exhibit molecular features of human basal-like breast cancer

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ATF3-Induced Mammary Tumors Exhibit Molecular Features of Human Basal-Like Breast Cancer.

Project description:Basal-like breast cancer (BLBC) is an aggressive and deadly subtype of human breast cancer that is highly metastatic, displays stem-cell like features, and has limited treatment options. Therefore, developing and characterizing preclinical mouse models with tumors that resemble BLBC is important for human therapeutic development. ATF3 is a potent oncogene that is aberrantly expressed in most human breast cancers. In the BK5.ATF3 mouse model, overexpression of ATF3 in the basal epithelial cells of the mammary gland produces tumors that are characterized by activation of the Wnt/β-catenin signaling pathway. Here, we used RNA-Seq and microRNA (miRNA) microarrays to better define the molecular features of BK5.ATF3-derived mammary tumors. These analyses showed that these tumors share many characteristics of human BLBC including reduced expression of Rb1, Esr1, and Pgr and increased expression of Erbb2, Egfr, and the genes encoding keratins 5, 6, and 17. An analysis of miRNA expression revealed reduced levels of Mir145 and Mir143, leading to the upregulation of their target genes including both the pluripotency factors Klf4 and Sox2 as well as the cancer stem-cell-related gene Kras. Finally, we show through knock-down experiments that ATF3 may directly modulate MIR145/143 expression. Taken together, our results indicate that the ATF3 mouse mammary tumor model could provide a powerful model to define the molecular mechanisms leading to BLBC, identify the factors that contribute to its aggressiveness, and, ultimately, discover specific genes and gene networks for therapeutic targeting.

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Project description:The WWOX gene has been implicated in human cancers, including breast cancer.The development and tumorigenesis between human and mouse mammary glands (MGs) share similar molecular details and signal transduction pathways. We established mouse line that specifically knockout the expression of WWOX gene in the MG epithelial cells (MECs) by crossing BK5-cre mice with our WWOX flox stain. In order to study the gene expression profile in the subpopulation MECs, we isolated the organoids from the 4th MGs of both BK5-cre +; WWOX flox/flox (KO) mice and their WT counterparts (BK5-cre -; WWOX flox/flox), 3 mice each genotype. The total RNA from the mouse MG organoids was extracted and purified by TRIzol/RNeasy Kit and their integrity was checked on Agilent RNA 6000 Nanochip. The goal is to identify the significant perturbation in tumorigenic pathways in these cells induced by WWOX ablation. Mammary gland epithelial organoids samples and gene expression profiles were deribed from three WWOX-KO mice (BK5-cre +; WWOX flox/flox) and from three WWOX-WT mice (BK5-cre -; WWOX flox/flox)

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Exercise-induced angiogenesis is dependent on metabolically primed ATF3/4+ endothelial cells

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Project description:This study examined the effect of early pregnancy on the gene expression profile of total isolated mammary epithelial cells in mice. Total mammary epithelial cells were isolated from parous and age-matched virgin control mice. Four independent replicates were assessed per treatment group, resulting in a total of 8 samples.

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Mammary transcriptome of rats treated with low-dose environmental chemicals from birth to adulthood

Project description:Exposure to common environmental chemicals, including those found in personal care products has been linked to mammary cancer at high doses in animal models. Their effects at low doses at levels comparable to human exposure remain poorly understood. Using a Sprague-Dawley rat model, we investigated the effects of three prevalently used environmental chemicals – diethyl phthalate (DEP), methyl paraben (MPB), triclosan (TCS) – and their mixture (MIX) on the transcriptome of normal developing mammary at levels mimicking human exposure. Rats were exposed from birth to adulthood in parous and nulliparous settings. We used affymetrix arrays to assess the influence of diethyl phthalate (DEP), methyl paraben (MPB), triclosan (TCS) and their mixture (MIX) on global gene expression profiles in rat mammary tissues, using doses comparable to human exposure. Exposure was from birth to adulthood (postnatal day 1 – 180) in parous and nulliparous rats.

2020-04-28 | GSE95554 | GEO

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