Novel RXR agonists differentially regulate gene transcription in mammary tumors of MMTV-neu mice
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PROVIDER: PRJNA869725 | ENA |
REPOSITORIES: ENA
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Project description:RXR agonists, which activate the RXR nuclear receptor, are effective in multiple preclinical cancer models for both treatment and prevention. While RXR is the target of these compounds, the downstream effects on gene expression differs between compounds. To elucidate the effects of the novel RXR agonist MSU 42011 on the transcriptome in tumors of MMTV-Neu mice, we performed RNA sequencing. For comparative analysis, RNA sequencing was also performed on tumors treated with the FDA approved RXR agonist bexarotene. Female MMTV-Neu mice with established mammary tumors 4 mm in diameter were fed control diet, bexarotene (100 mg/kg in diet), or MSU 42011 (100 mg/kg in diet) for 10 days. Both treatments differentially regulated cancer-relevant gene sets, such as focal adhesion, extracellular matrix, and immune pathways. Many of the top genes differentially regulated by RXR agonists are positively associated with survival in breast cancer patients. While MSU 42011 and bexarotene act on many common pathways, these experiments coupled with gene expression analysis of tumors treated with another novel RXR agonist V-125 highlight the differences in regulation of gene expression between these compounds of the same class. Exploration of these unique effects on gene transcription may lead to an increased understanding of the complex biology behind RXR agonists, and how the activities of this diverse class of compounds can be utilized to treat cancer.
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Project description:The objective of this study was to determine the effect of Thyroid Hormone Responsive Protein Spot14 (Spot14) overexpression on the gene expression profiles of tumors from MMTV-Neu mice. Hemizygous MMTV-Neu and MMTV-Spot14 mice were bred and 1 cm tumors from Neu control or Neu/Spot14 bitransgenic offspring were profiled using Affymetrix gene arrays. Tumors from Neu/Spot14 mice emerged significantly earlier than controls, but expressed many genes associated with lactogenic differentiation and were not highly metastatic. These results from the mouse model are consistent with observations from primary human breast tumors, which indicate that high Spot14 gene expression was directly correlated with a luminal subtype and a positive ER status. Overexpression of Spot14 in cultured mammary epithelial cells stimulated proliferation but not differentiation. Together, these data suggest that, in vivo, Spot14 is expressed in well-differentiated cells, and promotes the expansion of this population in the context of oncogenic signaling pathway activation. Microarray analysis was performed on 13 mammary tumors from MMTV-Neu mice and 9 tumors from MMTV-Neu/MMTV-Spot14 mice.
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Project description:Retinoid X receptor (RXR) agonists, which activate the RXR nuclear receptor, are effective in multiple preclinical cancer models for both treatment and prevention. While RXR is the direct target of these compounds, the downstream changes in gene expression differ between compounds. RNA sequencing was used to elucidate the effects of the novel RXRα agonist MSU-42011 on the transcriptome in mammary tumors of HER2+ mouse mammary tumor virus (MMTV)-Neu mice. For comparison, mammary tumors treated with the FDA approved RXR agonist bexarotene were also analyzed. Each treatment differentially regulated cancer-relevant gene categories, including focal adhesion, extracellular matrix, and immune pathways. The most prominent genes altered by RXR agonists positively correlate with survival in breast cancer patients. While MSU-42011 and bexarotene act on many common pathways, these experiments highlight the differences in gene expression between these two RXR agonists. MSU-42011 targets immune regulatory and biosynthetic pathways, while bexarotene acts on several proteoglycan and matrix metalloproteinase pathways. Exploration of these differential effects on gene transcription may lead to an increased understanding of the complex biology behind RXR agonists and how the activities of this diverse class of compounds can be utilized to treat cancer.
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