Transcriptomic signature of bexarotene (rexinoid LGD1069) on mammary gland from three transgenic mouse mammary cancer models
Martin C Abba1, Yuhui Hu, Carla C Levy
1Department of Carcinogenesis, The University of Texas M,D, Anderson Cancer Center, Science Park-Research Division, Smithville, 78957, TX, USA. mabba777@hotmail.com
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-null, 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.
Insights
Bexarotene, a retinoid X receptor (RXR) agonist, suppresses breast cancer development in mice. This study identified 9 core genes modulated by bexarotene, revealing its molecular mechanisms in breast cancer prevention.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Bexarotene is a selective retinoid X receptor (RXR) agonist that inhibits pre-malignant and malignant breast cell growth.
- It has demonstrated efficacy in suppressing breast cancer development in mouse models without adverse effects.
- Its chemopreventive effects are attributed to modulating cell proliferation, differentiation, and apoptosis.
Purpose of the Study:
- To profile genes modulated by bexarotene in the mammary gland of three distinct transgenic mouse models of breast cancer.
- To elucidate the molecular mechanisms underlying bexarotene's action.
- To identify potential biomarkers for bexarotene effectiveness.
Main Methods:
- Serial analysis of gene expression (SAGE) was utilized to analyze transcriptomes.
- Mammary cells from p53-null, MMTV-ErbB2, and C3(1)-SV40 transgenic mice treated with bexarotene and controls were profiled.
- Approximately 360,000 transcript tags were generated across 6 SAGE libraries.
Main Results:
- Gene expression profiling identified 89 dysregulated genes across the three models.
- A core set of 9 genes were commonly modulated by bexarotene in all three models.
- The study generated a comprehensive dataset of over 20,000 mRNAs.
Conclusions:
- Analysis of the common gene set revealed two key functional modules affected by bexarotene: protein biosynthesis and bioenergetics.
- These findings, along with targeting of cancer-related genes, provide insight into bexarotene's molecular mechanism.
- The identified core transcripts may serve as biomarkers for bexarotene's efficacy in breast cancer chemoprevention.
