Retinoid-induced growth arrest of breast carcinoma cells involves co-activation of multiple growth-inhibitory genes.
Retinoids are used in leukemia therapy and chemoprevention of cancers. Treatment of MCF-7 breast carcinoma cells with low doses of retinoids induces gradual proliferation arrest with phenotypic markers of senescence. cDNA microarray hybridization and reverse transcription-polymerase chain reaction analysis showed that retinoid-induced growth arrest in MCF-7 cells in associated with strong induction of 13 genes. Four of these genes (IGF-binding protein 3, EPLIN, beta IG-H3 and FAT10) have antiproliferative activity; EPLIN and beta IG-H3 are also known to be selectively inhibited in transformed relative to normal cells. The functions of the induced genes may also account for other cellular effects of retinoids, including the proteasome-mediated protein degradation, increased cell adhesion, and retinoic acid synthesis. Only one of 13 strongly induced genes (ring finger protein TRIM31) contains a putative retinoid response element in its promoter; TRIM31 also shows the most rapid kinetics of induction by retinoids. In contrast, the antiproliferative genes contain no identifiable retinoid response elements in their promoters and show more gradual induction kinetics, suggesting that these genes are indirectly induced by retinoids. Elucidation of the mechanisms that mediate co-induction of growth-inhibitory genes in retinoid-treated cells may suggest an approach to reproducing the growth-inhibitory effect of retinoids in retinoid-insensitive human cancers.
Dokmanovic
Milos
M
Department of Molecular Genetics, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, Illinois 60607-7170, USA.
Chang
Bey-Dih
BD
Fang
Jing
J
Roninson
Igor B
IB
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016326:Extracellular Matrix Proteins; D005260:Female; D017313:Fenretinide / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016212:Transforming Growth Factor beta; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology; D014452:Ubiquitins; D000099222:betaIG-H3 Protein
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins; D017313:Fenretinide; D006131:Growth Inhibitors; D018972:Insulin-Like Growth Factor Binding Protein 3; D009363:Neoplasm Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D014452:Ubiquitins; D000099222:betaIG-H3 Protein; C403263:LIMA1 protein, human; C109184:UBD protein, human