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A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase

Nature Medicine volume 5, pages 280–285 (1999)Cite this article

Abstract

Prostate cancer progresses from a hormone-sensitive, androgen-dependent stage to a hormone-refractory, androgen-independent tumor. The androgen receptor pathway functions in these androgen-independent tumors despite anti-androgen therapy. In our LAPC-4 prostate cancer model, androgen-independent sublines expressed higher levels of the HER-2/neu receptor tyrosine kinase than their androgen-dependent counterparts. Forced overexpression of HER-2/neu in androgen-dependent prostate cancer cells allowed ligand-independent growth. HER-2/neu activated the androgen receptor pathway in the absence of ligand and synergized with low levels of androgen to 'superactivate' the pathway. By modulating the response to low doses of androgen, a tyrosine kinase receptor can restore androgen receptor function to prostate cancer cells, a finding directly related to the clinical progression of prostate cancer.

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Figure 1: Expression of HER-2/neu in androgen-dependent and androgen-independent sublines of human prostate cancer xenografts.
Figure 2: Effect of HER-2/neu on growth of androgen-dependent prostate cancer cells in vitro in the absence of androgen.
Figure 3: Effect of HER-2/neu overexpression on tumorigenicity of prostate cancer cells in intact and castrated male SCID mice.
Figure 4: Effect of HER-2/neu on levels of the androgen-regulated PSA protein.
Figure 5: Effects of HER-2/neu on androgen-dependent PSA transcription.
Figure 6: Effects of HER-2/neu on androgen receptor function.

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Acknowledgements

We thank J. Redula and C. Tran for assistance with animal experiments, A. Raitano for advice during the early phases of this work, D. Slamon and A. Belldegrun for reagents and D. Reese for discussions. This work was supported by grants from CaP CURE, the Margaret Early Trust and the James S. McDonnell Foundation and NIH #GM08042.

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Authors and Affiliations

  1. Departments of Medicine, University of California, 10833 Le Conte Avenue, 11-934 Factor Building, Los Angeles, 90095, California, USA

    Noah Craft & Charles L. Sawyers

  2. Biological Chemistry, University of California,, 10833 Le Conte Avenue, 11-934 Factor Building, Los Angeles, 90095, California, USA

    Yuriy Shostak & Michael Carey

  3. Molecular Biology Institute, University of California,, 10833 Le Conte Avenue, 11-934 Factor Building, Los Angeles, 90095, California, USA

    Noah Craft, Michael Carey & Charles L. Sawyers

  4. Hematology-Oncology, University of California,, 10833 Le Conte Avenue, 11-934 Factor Building, Los Angeles, 90095, California, USA

    Charles L. Sawyers

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Correspondence to Charles L. Sawyers.

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Craft, N., Shostak, Y., Carey, M. et al. A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med 5, 280–285 (1999). https://doi.org/10.1038/6495

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