Abstract
The human retinoic acid receptor beta (RARbeta) has three isoforms (beta1, beta2, and beta4), which play important, distinct roles in mediating the effects of retinoic acid on cell growth and apoptosis. Whereas RARbeta2 is a potent inhibitor of breast cancer cell proliferation, RARbeta4 can act as a dominant-negative repressor of RARbeta2-mediated growth suppression. In this study we investigated the effects of all-trans-retinoic acid (ATRA) on two clones derived from the breast cancer cell line MDA-MB-435: a non-metastatic clone (NM-2C5) and a metastatic clone (M-4A4). ATRA treatment of the NM-2C5 cells resulted in growth inhibition and apoptosis, whereas the M-4A4 cells were resistant to ATRA. Analyses of the expression of RARbeta isoforms revealed that the sensitive NM-2C5 clone expressed only RARbeta2, whereas the resistant M-4A4 cells expressed both RARbeta2 and RARbeta4 mRNA and protein. ATRA treatment increased RARbeta2 mRNA level in NM-2C5 cells, whereas the same treatment of the M-4A4 cells resulted in an increase in RARbeta4 and a decrease in RARbeta2 mRNA. ATRA treatment of NM-2C5 cells increased the protein levels of the histone acetyl transferases p300 and CBP, suppressed the level of histone deacetylase and increased the level of acetylated histone H4. ATRA also decreased Bcl-2 and increased Bax and decreased VEGF. In contrast, the same treatment of the M-4A4 cells resulted in opposite effects. These results suggest that the effects of ATRA on the growth of the metastatic and non-metastatic breast cancer cell lines depend on the expression of RARbeta isoforms and that the expression of RARbeta4 may contribute to metastatic properties.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / pathology*
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Adenocarcinoma / secondary
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Breast Neoplasms / genetics
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Breast Neoplasms / pathology*
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Cell Division / drug effects
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Cell Line, Tumor / drug effects
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Cell Line, Tumor / pathology
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Clone Cells / drug effects
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Clone Cells / pathology
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Drug Resistance, Neoplasm / genetics
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Enzyme Induction / drug effects
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Female
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Gene Expression Regulation, Neoplastic / drug effects*
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Genes, bcl-2
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Histone Deacetylases / biosynthesis
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Histone Deacetylases / genetics
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Histones / biosynthesis
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Histones / genetics
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Humans
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Neoplasm Metastasis / genetics*
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Neoplasm Proteins / biosynthesis*
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Neoplasm Proteins / genetics
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Nuclear Proteins / biosynthesis
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Nuclear Proteins / genetics
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Protein Isoforms / biosynthesis
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Protein Isoforms / genetics
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Protein Isoforms / physiology
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Receptors, Retinoic Acid / biosynthesis*
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Receptors, Retinoic Acid / genetics
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Receptors, Retinoic Acid / physiology
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Trans-Activators / biosynthesis
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Trans-Activators / genetics
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Tretinoin / pharmacology*
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Vascular Endothelial Growth Factor A / biosynthesis
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Vascular Endothelial Growth Factor A / genetics
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bcl-2-Associated X Protein
Substances
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Antineoplastic Agents
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BAX protein, human
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Histones
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Neoplasm Proteins
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Nuclear Proteins
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Protein Isoforms
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Retinoic Acid
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Trans-Activators
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Vascular Endothelial Growth Factor A
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bcl-2-Associated X Protein
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retinoic acid receptor beta
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Tretinoin
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Histone Deacetylases