Abstract
BackgroundThe rexinoid bexarotene (LGD1069, Targretin) is a highly selective retinoid × 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.MethodsSerial 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.ResultsThis 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.ConclusionAnalysis 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.
Highlights
The rexinoid bexarotene (LGD1069, Targretin) is a highly selective retinoid × receptor (RXR) agonist that inhibits the growth of pre-malignant and malignant breast cells
In an effort to elucidate the molecular mechanism of action of chemopreventive rexinoid bexarotene and to identify potential biomarkers of significance, here we report a comparative transcriptome profiling of three mouse mammary cancer models by Serial Analysis of Gene Expression (SAGE)
The chemopreventive effects of bexarotene are likely due to transcriptional modulation of genes related to repression of cell proliferation and stimulation of apoptosis and cell differentiation [19]
Summary
The rexinoid bexarotene (LGD1069, Targretin) is a highly selective retinoid × 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. 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. Two-thirds of all breast cancers are ERα (+) at the time of diagnosis and expression of this receptor is determinant of a tumor phenotype that is associated with hormone-responsiveness. Despite the effectiveness of anti-estrogen selective ER modulators (tamoxifen and raloxifene) for ERα (+) breast cancer treatment, there is a clear need to develop agents for the prevention and treatment of ERα (-) breast cancer. Mammary tumors arising in transgenic mice are generally ERα (-) providing a useful system for testing chemopreventive agents against hormonally non-responsive tumors
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