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RAR agonists stimulate SOX9 gene expression in breast cancer cell lines: evidence for a role in retinoid-mediated growth inhibition

Oncogene volumeĀ 21,Ā pages 7850ā€“7860 (2002)Cite this article

Abstract

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 RARĪ±-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.

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Acknowledgements

We are grateful to Dr Benoit de Crombrugghe for providing us with SOX9 plasmids and antibody to SOX9. This research was supported by NIH grant D16636 (HH Samuels), a New York State Department of Health Breast Cancer Award (C015710) (HH Samuels), a Robert Wood Johnson Foundation Grant (038398) (O Afonja), and NIH Grant K12CA01713 (O Afonja).

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Author notes

  1. Bruce M Raaka

    Present address: NIDDK Diabetes Branch, Receptor and Hormone Action Section, National Institutes of Health MSC 8029, Bethesda, 20892, Maryland, MD, USA

Authors and Affiliations

  1. Department of Pediatrics, New York University School of Medicine, 550 First Avenue, New York, 10016, New York, NY, USA

    Olubunmi AfonjaĀ &Ā Dominique Juste

  2. Department of Pharmacology, New York University School of Medicine, 550 First Avenue, New York, 10016, New York, NY, USA

    Bruce M Raaka,Ā Ambrose Huang,Ā Sharmistha Das,Ā Xinyu ZhaoĀ &Ā Herbert H Samuels

  3. Department of Biology, Long Island University, One University Plaza, Brooklyn, 11201, New York, NY, USA

    Elizabeth Helmer

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Correspondence to Herbert H Samuels.

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Afonja, O., Raaka, B., Huang, A. et al. RAR agonists stimulate SOX9 gene expression in breast cancer cell lines: evidence for a role in retinoid-mediated growth inhibition. Oncogene 21, 7850ā€“7860 (2002). https://doi.org/10.1038/sj.onc.1205985

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