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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

Graph of interactions among the common core of genes modulated by rexinoid bexarotene in the different mammary mice genetic models generated using database STRING. Genes without known interactions with other genes are listed in the left of the figure. In the network: links between proteins means the various interactions data supporting the network, colored by evidence type.
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Figure 4: Graph of interactions among the common core of genes modulated by rexinoid bexarotene in the different mammary mice genetic models generated using database STRING. Genes without known interactions with other genes are listed in the left of the figure. In the network: links between proteins means the various interactions data supporting the network, colored by evidence type.

Mentions: We present in Figure 4 a protein-protein interaction network associating the common core of non-random bexarotene modulated genes across transgenic mouse mammary models. The graph was generated employing the STRING on-line resource based on high confidence data related with 'co-expression/co-ocurrence', 'experimental/biochemical data' and 'association in curated database/text mining' [17]. STRING is a comprehensive tool integrating protein association information with the capability to transfer known interactions from model organisms to other species (e.g.: from mouse to human orthology genes/proteins) based on predicted orthology of the respective proteins. The generated graph (Figure 4) indicates strong interactions among a set of 33 proteins transcriptionally modulated by bexarotene. Furthermore, the network architecture suggests the existence of two functional modules in this figure, involving the down-modulation of genes related with protein biosynthesis pathway, and up-modulation of genes related with tricarboxylic acid cycle/oxidative phosphorilation pathways.


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)

Graph of interactions among the common core of genes modulated by rexinoid bexarotene in the different mammary mice genetic models generated using database STRING. Genes without known interactions with other genes are listed in the left of the figure. In the network: links between proteins means the various interactions data supporting the network, colored by evidence type.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Graph of interactions among the common core of genes modulated by rexinoid bexarotene in the different mammary mice genetic models generated using database STRING. Genes without known interactions with other genes are listed in the left of the figure. In the network: links between proteins means the various interactions data supporting the network, colored by evidence type.
Mentions: We present in Figure 4 a protein-protein interaction network associating the common core of non-random bexarotene modulated genes across transgenic mouse mammary models. The graph was generated employing the STRING on-line resource based on high confidence data related with 'co-expression/co-ocurrence', 'experimental/biochemical data' and 'association in curated database/text mining' [17]. STRING is a comprehensive tool integrating protein association information with the capability to transfer known interactions from model organisms to other species (e.g.: from mouse to human orthology genes/proteins) based on predicted orthology of the respective proteins. The generated graph (Figure 4) indicates strong interactions among a set of 33 proteins transcriptionally modulated by bexarotene. Furthermore, the network architecture suggests the existence of two functional modules in this figure, involving the down-modulation of genes related with protein biosynthesis pathway, and up-modulation of genes related with tricarboxylic acid cycle/oxidative phosphorilation pathways.

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