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Transcriptomic signature of bexarotene (rexinoid LGD1069) on mammary gland from three transgenic mouse mammary cancer models.

Abba MC, Hu Y, Levy CC, Gaddis S, Kittrell FS, Zhang Y, Hill J, Bissonnette RP, Medina D, Brown PH, Aldaz CM - BMC Med Genomics (2008)

Bottom Line: The chemopreventive effects of bexarotene are due to transcriptional modulation of cell proliferation, differentiation and apoptosis.This resulted in a dataset of approximately 360,000 transcript tags representing over 20,000 mRNAs from a total of 6 different SAGE libraries.Analysis of the indicated core of transcripts and protein-protein interactions of this commonly modulated genes indicate two functional modules significantly affected by rexinoid bexarotene related to protein biosynthesis and bioenergetics signatures, in addition to the targeting of cancer-causing genes related with cell proliferation, differentiation and apoptosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Carcinogenesis, The University of Texas M,D, Anderson Cancer Center, Science Park-Research Division, Smithville, 78957, TX, USA. mabba777@hotmail.com

ABSTRACT

Background: The rexinoid bexarotene (LGD1069, Targretin) is a highly selective retinoid x receptor (RXR) agonist that inhibits the growth of pre-malignant and malignant breast cells. Bexarotene was shown to suppress the development of breast cancer in transgenic mice models without side effects. The chemopreventive effects of bexarotene are due to transcriptional modulation of cell proliferation, differentiation and apoptosis. Our goal in the present study was to obtain a profile of the genes modulated by bexarotene on mammary gland from three transgenic mouse mammary cancer models in an effort to elucidate its molecular mechanism of action and for the identification of biomarkers of effectiveness.

Methods: Serial analysis of gene expression (SAGE) was employed to profile the transcriptome of p53-, MMTV-ErbB2, and C3(1)-SV40 mammary cells obtained from mice treated with bexarotene and their corresponding controls.

Results: This resulted in a dataset of approximately 360,000 transcript tags representing over 20,000 mRNAs from a total of 6 different SAGE libraries. Analysis of gene expression changes induced by bexarotene in mammary gland revealed that 89 genes were dysregulated among the three transgenic mouse mammary models. From these, 9 genes were common to the three models studied.

Conclusion: Analysis of the indicated core of transcripts and protein-protein interactions of this commonly modulated genes indicate two functional modules significantly affected by rexinoid bexarotene related to protein biosynthesis and bioenergetics signatures, in addition to the targeting of cancer-causing genes related with cell proliferation, differentiation and apoptosis.

No MeSH data available.


Related in: MedlinePlus

Candidate genes and pathways modulated in normal mammary epithelium by rexinoid bexarotene in three different transgenic mice mammary cell models were identified through a three-stage process:A. Identification of differentially expressed genes in mammary gland as a result of treatment with bexarotene comparing with vehicle control, in each of the mammary cancer models B. Inter-model comparison for the identification of overlapping gene expression profiles. C. Identification of associated functional modules and pathways affected by bexarotene treatment.
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Figure 1: Candidate genes and pathways modulated in normal mammary epithelium by rexinoid bexarotene in three different transgenic mice mammary cell models were identified through a three-stage process:A. Identification of differentially expressed genes in mammary gland as a result of treatment with bexarotene comparing with vehicle control, in each of the mammary cancer models B. Inter-model comparison for the identification of overlapping gene expression profiles. C. Identification of associated functional modules and pathways affected by bexarotene treatment.

Mentions: The main strategy of this analysis was to identify commonly deregulated genes by bexarotene treatment among the different mammary cancer models tested (Figure 1). Differentially expressed genes were compiled into one Excel spreadsheet pivot Table for comparison of overlapping data between p53-, MMTV-erbB2 and C3(1)/SV40 T-antigen transgenic mouse mammary models. Any combination of two lists was compared for matching gene-identity. The number and identity of genes commonly affected in two models (e.g. MMTV-erbB2 vs. p53-) was determined. We used the normal approximation to the binomial distribution as previously described [14] to calculate whether the number of matching genes derived from each pairwise comparison was of statistical significance (p < 0.05). To enable illustration of the commonly deregulated genes between mammary cancer models, we used the TIGR MultiExperiment Viewer (MeV 3.0) software. This tool was used for average clustering of SAGE based on the fold change of tag counts for each transcript comparing bexarotene treatment to control (vehicle) in each transgenic mice mammary model. For automated functional annotation and classification of genes of interest based on Gene Ontology (GO) terms, we used the EASE [15] available at the Database for Annotation, Visualization and Integrated Discovery (DAVID) [16]. All of the raw SAGE data reported as additional files in this article are publicly available and also can be viewed at .


Transcriptomic signature of bexarotene (rexinoid LGD1069) on mammary gland from three transgenic mouse mammary cancer models.

Abba MC, Hu Y, Levy CC, Gaddis S, Kittrell FS, Zhang Y, Hill J, Bissonnette RP, Medina D, Brown PH, Aldaz CM - BMC Med Genomics (2008)

Candidate genes and pathways modulated in normal mammary epithelium by rexinoid bexarotene in three different transgenic mice mammary cell models were identified through a three-stage process:A. Identification of differentially expressed genes in mammary gland as a result of treatment with bexarotene comparing with vehicle control, in each of the mammary cancer models B. Inter-model comparison for the identification of overlapping gene expression profiles. C. Identification of associated functional modules and pathways affected by bexarotene treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2563021&req=5

Figure 1: Candidate genes and pathways modulated in normal mammary epithelium by rexinoid bexarotene in three different transgenic mice mammary cell models were identified through a three-stage process:A. Identification of differentially expressed genes in mammary gland as a result of treatment with bexarotene comparing with vehicle control, in each of the mammary cancer models B. Inter-model comparison for the identification of overlapping gene expression profiles. C. Identification of associated functional modules and pathways affected by bexarotene treatment.
Mentions: The main strategy of this analysis was to identify commonly deregulated genes by bexarotene treatment among the different mammary cancer models tested (Figure 1). Differentially expressed genes were compiled into one Excel spreadsheet pivot Table for comparison of overlapping data between p53-, MMTV-erbB2 and C3(1)/SV40 T-antigen transgenic mouse mammary models. Any combination of two lists was compared for matching gene-identity. The number and identity of genes commonly affected in two models (e.g. MMTV-erbB2 vs. p53-) was determined. We used the normal approximation to the binomial distribution as previously described [14] to calculate whether the number of matching genes derived from each pairwise comparison was of statistical significance (p < 0.05). To enable illustration of the commonly deregulated genes between mammary cancer models, we used the TIGR MultiExperiment Viewer (MeV 3.0) software. This tool was used for average clustering of SAGE based on the fold change of tag counts for each transcript comparing bexarotene treatment to control (vehicle) in each transgenic mice mammary model. For automated functional annotation and classification of genes of interest based on Gene Ontology (GO) terms, we used the EASE [15] available at the Database for Annotation, Visualization and Integrated Discovery (DAVID) [16]. All of the raw SAGE data reported as additional files in this article are publicly available and also can be viewed at .

Bottom Line: The chemopreventive effects of bexarotene are due to transcriptional modulation of cell proliferation, differentiation and apoptosis.This resulted in a dataset of approximately 360,000 transcript tags representing over 20,000 mRNAs from a total of 6 different SAGE libraries.Analysis of the indicated core of transcripts and protein-protein interactions of this commonly modulated genes indicate two functional modules significantly affected by rexinoid bexarotene related to protein biosynthesis and bioenergetics signatures, in addition to the targeting of cancer-causing genes related with cell proliferation, differentiation and apoptosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Carcinogenesis, The University of Texas M,D, Anderson Cancer Center, Science Park-Research Division, Smithville, 78957, TX, USA. mabba777@hotmail.com

ABSTRACT

Background: The rexinoid bexarotene (LGD1069, Targretin) is a highly selective retinoid x receptor (RXR) agonist that inhibits the growth of pre-malignant and malignant breast cells. Bexarotene was shown to suppress the development of breast cancer in transgenic mice models without side effects. The chemopreventive effects of bexarotene are due to transcriptional modulation of cell proliferation, differentiation and apoptosis. Our goal in the present study was to obtain a profile of the genes modulated by bexarotene on mammary gland from three transgenic mouse mammary cancer models in an effort to elucidate its molecular mechanism of action and for the identification of biomarkers of effectiveness.

Methods: Serial analysis of gene expression (SAGE) was employed to profile the transcriptome of p53-, MMTV-ErbB2, and C3(1)-SV40 mammary cells obtained from mice treated with bexarotene and their corresponding controls.

Results: This resulted in a dataset of approximately 360,000 transcript tags representing over 20,000 mRNAs from a total of 6 different SAGE libraries. Analysis of gene expression changes induced by bexarotene in mammary gland revealed that 89 genes were dysregulated among the three transgenic mouse mammary models. From these, 9 genes were common to the three models studied.

Conclusion: Analysis of the indicated core of transcripts and protein-protein interactions of this commonly modulated genes indicate two functional modules significantly affected by rexinoid bexarotene related to protein biosynthesis and bioenergetics signatures, in addition to the targeting of cancer-causing genes related with cell proliferation, differentiation and apoptosis.

No MeSH data available.


Related in: MedlinePlus