Preventive efficacy of receptor class selective retinoids on HER-2/neu oncogene expressing preneoplastic human mammary epithelial cells

  • Authors:
    • H. Jinno
    • M. G. Steiner
    • K. Nason-Burchenal
    • M. P. Osborne
    • N. T. Telang
  • View Affiliations

  • Published online on: July 1, 2002     https://doi.org/10.3892/ijo.21.1.127
  • Pages: 127-134
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Abstract

Aberrant proliferation is an early-occurring event in vitro prior to tumorigenesis in vivo in the multistep process of carcinogenesis. Inhibition of aberrant proliferation therefore may represent a useful biomarker to evaluate the efficacy of chemopreventive agents. Retinoids have exhibited preventive efficacy in vitro and in vivo predominantly through the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Clinically relevant biochemical and cellular mechanistic endpoints for chemopreventive effects of retinoids should provide novel biomarkers. The present study was designed to examine the preventive efficacy of natural retinoids, all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid (9cisRA), and to identify the possible mechanisms for their effects using the HER-2/neu oncogene expressing preneoplastic human mammary epithelial 184-B5/HER cells. Seven-day treatment with ATRA and 9cisRA exhibited a dose-dependent growth inhibition. Long-term (21 days) treatment with IC20 doses of 50 nM ATRA and 100 nM 9cisRA inhibited anchorage-dependent colony forming efficiency by about 75.4% (p<0.01) and 84.9% (p<0.01), respectively. Cell cycle analysis revealed that a 24-h treatment with IC90 doses of 2 μM ATRA and 3 μM 9cisRA accumulates cells in the G0/G1 phase and inhibit S and/or G2/M phase of the cell cycle. ATRA and 9cisRA induced an 11-fold (p=0.03) and a 9-fold (p=0.04) increase in subG0/G1 (apoptotic) population relative to the solvent control, respectively. ATRA and 9cisRA induced 77% (p=0.01) and 51% (p=0.02) decrease in tyrosine kinase immunoreactivity, respectively. Similarly, the two retinoids caused almost a 50% (p=0.01) down-regulation of Bcl-2 immunoreactivity. Western blot analysis revealed that ATRA induced an increase in RARβ expression and a decrease in RARγ expression, while 9cisRA down-regulated RXRα expression. These data demonstrate that ATRA and 9cisRA may inhibit HER-2/neu induced aberrant proliferation in part by retarding cell cycle progression, down-regulating HER-2/neu-mediated signal transduction and inducing Bcl-2-dependent apoptosis through a retinoid receptor-mediated mechanism.

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July 2002
Volume 21 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Jinno H, Steiner MG, Nason-Burchenal K, Osborne MP and Telang NT: Preventive efficacy of receptor class selective retinoids on HER-2/neu oncogene expressing preneoplastic human mammary epithelial cells. Int J Oncol 21: 127-134, 2002
APA
Jinno, H., Steiner, M.G., Nason-Burchenal, K., Osborne, M.P., & Telang, N.T. (2002). Preventive efficacy of receptor class selective retinoids on HER-2/neu oncogene expressing preneoplastic human mammary epithelial cells. International Journal of Oncology, 21, 127-134. https://doi.org/10.3892/ijo.21.1.127
MLA
Jinno, H., Steiner, M. G., Nason-Burchenal, K., Osborne, M. P., Telang, N. T."Preventive efficacy of receptor class selective retinoids on HER-2/neu oncogene expressing preneoplastic human mammary epithelial cells". International Journal of Oncology 21.1 (2002): 127-134.
Chicago
Jinno, H., Steiner, M. G., Nason-Burchenal, K., Osborne, M. P., Telang, N. T."Preventive efficacy of receptor class selective retinoids on HER-2/neu oncogene expressing preneoplastic human mammary epithelial cells". International Journal of Oncology 21, no. 1 (2002): 127-134. https://doi.org/10.3892/ijo.21.1.127