Downregulation of retinoblastoma protein is involved in the enhanced cytotoxicity of 4-hydroxytamoxifen plus mifepristone combination therapy versus antiestrogen monotherapy of human breast cancer

  • Authors:
    • Patricia V. Schoenlein
    • Min Hou
    • Julia S. Samaddar
    • Virgil T. Gaddy
    • Muthusamy Thangaraju
    • Jill Lewis
    • Maribeth Johnson
    • Vadivel Ganapathy
    • Andre Kallab
    • John T. Barrett
  • View Affiliations

  • Published online on: September 1, 2007     https://doi.org/10.3892/ijo.31.3.643
  • Pages: 643-655
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Abstract

In this study, human MCF-7 breast cancer cells, which express functional estrogen and progesterone receptors, were used to compare the efficacy of combined antiestrogen plus antiprogestin therapy to antiestrogen monotherapy. Cells were treated with the antiestrogen 4-hydroxytamoxifen (4-OHT) and/or the antiprogestin mifepristone (MIF) and effects on cell proliferation (cytostatic action), cell cycle phase, the phosphorylation state of the tumor suppressor retinoblastoma protein (Rb), and induction of active cell death (cytotoxic action) were determined. Combination hormonal therapy showed both increased cytostatic and cytotoxic activity as compared to either monotherapy. The increased cytostatic action was mediated by Rb activation; whereas, the cytotoxic (pro-apoptotic) action of combined hormonal therapy correlated to a significant reduction in Rb protein levels. To test the apparent role of Rb protein loss in the pro-apoptotic action of combined hormonal therapy, Rb was downregulated in MCF-7 cells using siRNA-targeting. The siRNA-mediated knockdown of Rb combined with 4-OHT therapy resulted in a pro-apoptotic action similar to that resulting from 4-OHT and MIF combination treatment, which included increased cell detachment from the monolayer, high-molecular-weight genomic DNA fragmentation, and cleavage of poly ADP-ribose polymerase (PARP) and lamin A. From these studies, we conclude that Rb protein downregulation is required for 4-OHT-treated, estrogen receptor positive (ER+) breast cancer cells to undergo active cell death. We discuss the potential of using an antiprogestin such as MIF plus antiestrogen treatment to more effectively downregulate Rb in ER+ breast cancer cells to increase the overall cytotoxic action of hormonal therapy.

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September 2007
Volume 31 Issue 3

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

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Spandidos Publications style
Schoenlein PV, Hou M, Samaddar JS, Gaddy VT, Thangaraju M, Lewis J, Johnson M, Ganapathy V, Kallab A, Barrett JT, Barrett JT, et al: Downregulation of retinoblastoma protein is involved in the enhanced cytotoxicity of 4-hydroxytamoxifen plus mifepristone combination therapy versus antiestrogen monotherapy of human breast cancer. Int J Oncol 31: 643-655, 2007
APA
Schoenlein, P.V., Hou, M., Samaddar, J.S., Gaddy, V.T., Thangaraju, M., Lewis, J. ... Barrett, J.T. (2007). Downregulation of retinoblastoma protein is involved in the enhanced cytotoxicity of 4-hydroxytamoxifen plus mifepristone combination therapy versus antiestrogen monotherapy of human breast cancer. International Journal of Oncology, 31, 643-655. https://doi.org/10.3892/ijo.31.3.643
MLA
Schoenlein, P. V., Hou, M., Samaddar, J. S., Gaddy, V. T., Thangaraju, M., Lewis, J., Johnson, M., Ganapathy, V., Kallab, A., Barrett, J. T."Downregulation of retinoblastoma protein is involved in the enhanced cytotoxicity of 4-hydroxytamoxifen plus mifepristone combination therapy versus antiestrogen monotherapy of human breast cancer". International Journal of Oncology 31.3 (2007): 643-655.
Chicago
Schoenlein, P. V., Hou, M., Samaddar, J. S., Gaddy, V. T., Thangaraju, M., Lewis, J., Johnson, M., Ganapathy, V., Kallab, A., Barrett, J. T."Downregulation of retinoblastoma protein is involved in the enhanced cytotoxicity of 4-hydroxytamoxifen plus mifepristone combination therapy versus antiestrogen monotherapy of human breast cancer". International Journal of Oncology 31, no. 3 (2007): 643-655. https://doi.org/10.3892/ijo.31.3.643