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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

Co-occurring differentially expressed genes among transgenic mouse mammary models. Eighty-nine genes were identified as modulated in more than one transgenic mice model. A. Heat map of the 89 deregulated transcripts. Color scale at the bottom depicts the approximate fold change in expression for each transcript and library relative to control mammary gland. Negative fold change (transcripts with decreased expression in bexarotene treated animals) is represented in green, and positive fold change (transcripts with overexpression in bexarotene treated mice) is represented in red. B. Statistical comparison between MMTV-erbB2 vs. p53- and MMTV-erbB2 vs. C3(1)/SV40 T-antigen transgenic mice models showing a highly significant number of overlapping genes (p < 0.001). The number of overlapping genes between p53- and C3(1) SV40 models it is not statistical significant (p > 0.05).
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Figure 3: Co-occurring differentially expressed genes among transgenic mouse mammary models. Eighty-nine genes were identified as modulated in more than one transgenic mice model. A. Heat map of the 89 deregulated transcripts. Color scale at the bottom depicts the approximate fold change in expression for each transcript and library relative to control mammary gland. Negative fold change (transcripts with decreased expression in bexarotene treated animals) is represented in green, and positive fold change (transcripts with overexpression in bexarotene treated mice) is represented in red. B. Statistical comparison between MMTV-erbB2 vs. p53- and MMTV-erbB2 vs. C3(1)/SV40 T-antigen transgenic mice models showing a highly significant number of overlapping genes (p < 0.001). The number of overlapping genes between p53- and C3(1) SV40 models it is not statistical significant (p > 0.05).

Mentions: In order to identify co-occurring differentially expressed genes among the three transgenic mice analyses, we performed an inter-model comparison between the above-described SAGE datasets (Figure 1). Among the three mice mammary models, a total of 711 transcripts were identified as deregulated by the rexinoid bexarotene treatment. Eighty-nine genes were identified in more than one mammary cancer model (Figure 3A; see Additional file 2). Interestingly, nine of these 89 genes were deregulated by bexarotene in mammary gland tissue from all three transgenic models: Muc15 (Mucin 15), Cdo1 (Cystein dioxygenase 1), Rps8 (Ribosomal protein S28), Rps27 (Ribosomal protein S27), Rps24 (Ribosomal protein S24), Hspa5 (Heat shock 70 kD protein 5), Csrp1 (Cysteine and glycine-rich protein 1), Npm1 (Nucleophosmin 1), and Cycs (Cytochrome c somatic). Gene Ontology annotation of the 89 deregulated genes that were common in any two models showed that approximately 18% of the transcripts are involved in tricarboxylic acid cycle/oxidative phosphorylation, 14% are related to signal transduction/transcriptional regulation, 14% are related to protein metabolism and 12% are related to cell proliferation/differentiation and apoptosis.


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)

Co-occurring differentially expressed genes among transgenic mouse mammary models. Eighty-nine genes were identified as modulated in more than one transgenic mice model. A. Heat map of the 89 deregulated transcripts. Color scale at the bottom depicts the approximate fold change in expression for each transcript and library relative to control mammary gland. Negative fold change (transcripts with decreased expression in bexarotene treated animals) is represented in green, and positive fold change (transcripts with overexpression in bexarotene treated mice) is represented in red. B. Statistical comparison between MMTV-erbB2 vs. p53- and MMTV-erbB2 vs. C3(1)/SV40 T-antigen transgenic mice models showing a highly significant number of overlapping genes (p < 0.001). The number of overlapping genes between p53- and C3(1) SV40 models it is not statistical significant (p > 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Co-occurring differentially expressed genes among transgenic mouse mammary models. Eighty-nine genes were identified as modulated in more than one transgenic mice model. A. Heat map of the 89 deregulated transcripts. Color scale at the bottom depicts the approximate fold change in expression for each transcript and library relative to control mammary gland. Negative fold change (transcripts with decreased expression in bexarotene treated animals) is represented in green, and positive fold change (transcripts with overexpression in bexarotene treated mice) is represented in red. B. Statistical comparison between MMTV-erbB2 vs. p53- and MMTV-erbB2 vs. C3(1)/SV40 T-antigen transgenic mice models showing a highly significant number of overlapping genes (p < 0.001). The number of overlapping genes between p53- and C3(1) SV40 models it is not statistical significant (p > 0.05).
Mentions: In order to identify co-occurring differentially expressed genes among the three transgenic mice analyses, we performed an inter-model comparison between the above-described SAGE datasets (Figure 1). Among the three mice mammary models, a total of 711 transcripts were identified as deregulated by the rexinoid bexarotene treatment. Eighty-nine genes were identified in more than one mammary cancer model (Figure 3A; see Additional file 2). Interestingly, nine of these 89 genes were deregulated by bexarotene in mammary gland tissue from all three transgenic models: Muc15 (Mucin 15), Cdo1 (Cystein dioxygenase 1), Rps8 (Ribosomal protein S28), Rps27 (Ribosomal protein S27), Rps24 (Ribosomal protein S24), Hspa5 (Heat shock 70 kD protein 5), Csrp1 (Cysteine and glycine-rich protein 1), Npm1 (Nucleophosmin 1), and Cycs (Cytochrome c somatic). Gene Ontology annotation of the 89 deregulated genes that were common in any two models showed that approximately 18% of the transcripts are involved in tricarboxylic acid cycle/oxidative phosphorylation, 14% are related to signal transduction/transcriptional regulation, 14% are related to protein metabolism and 12% are related to cell proliferation/differentiation and apoptosis.

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