RAR agonists stimulate SOX9 gene expression in breast cancer cell lines: evidence for a role in retinoid-mediated growth inhibition.
Retinoic acid receptors (RARs) are ligand-dependent transcription factors which are members of the steroid/thyroid hormone receptor gene family. RAR-agonists inhibit the proliferation of many human breast cancer cell lines, particularly those whose growth is stimulated by estradiol (E2) or growth factors. PCR-amplified subtractive hybridization was used to identify candidate retinoid-regulated genes that may be involved in growth inhibition. One candidate gene identified was SOX9, a member of the high mobility group (HMG) box gene family of transcription factors. SOX9 gene expression is rapidly stimulated by RAR-agonists in T-47D cells and other retinoid-inhibited breast cancer cell lines. In support of this finding, a database search indicates that SOX9 is expressed as an EST in breast tumor cells. SOX9 is known to be expressed in chondrocytes where it regulates the transcription of type II collagen and in testes where it plays a role in male sexual differentiation. RAR pan-agonists and the RARalpha-selective agonist Am580, but not RXR agonists, stimulate the expression of SOX9 in a wide variety of retinoid-inhibited breast cancer cell lines. RAR-agonists did not stimulate SOX9 in breast cancer cell lines which were not growth inhibited by retinoids. Expression of SOX9 in T-47D cells leads to cycle changes similar to those found with RAR-agonists while expression of a dominant negative form of SOX9 blocks RA-mediated cell cycle changes, suggesting a role for SOX9 in retinoid-mediated growth inhibition.
Afonja
Olubunmi
O
Department of Pediatrics, New York University School of Medicine, 550 First Avenue, New York, New York, NY 10016, USA.
Raaka
Bruce M
BM
Huang
Ambrose
A
Das
Sharmistha
S
Zhao
Xinyu
X
Helmer
Elizabeth
E
Juste
Dominique
D
Samuels
Herbert H
HH
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens; D020224:Expressed Sequence Tags; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018390:Gene Targeting; D005799:Genes, Dominant; D006133:Growth Substances / Q000494:pharmacology; D006609:High Mobility Group Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D008321:Mammary Glands, Animal / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D011960:Receptors, Estrogen / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000494:pharmacology*; D055758:SOX9 Transcription Factor; D013737:Testis / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D001565:Benzoates; D004967:Estrogens; D006133:Growth Substances; D006609:High Mobility Group Proteins; D009363:Neoplasm Proteins; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C527933:Sox9 protein, mouse; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; C068073:Am 580; D004958:Estradiol; D014212:Tretinoin