Nature Medicine
5, 280 - 285 (1999)
doi:10.1038/6495
A mechanism for hormone-independent prostate cancer through modulation
of androgen receptor signaling by the HER-2/neu tyrosine kinaseNoah Craft1, 3, Yuriy Shostak2, Michael Carey2, 3
& Charles L. Sawyers1, 3, 41
Departments of Medicine, University of California,
10833 Le Conte Avenue, 11-934 Factor Building,
Los Angeles, California 90095, USA
2
Biological Chemistry, University of California,
10833 Le Conte Avenue, 11-934 Factor Building, Los Angeles,
California 90095, USA
3
Molecular Biology Institute, University of California,
10833 Le Conte Avenue, 11-934 Factor Building,
Los Angeles, California 90095, USA
4
Hematology-Oncology, University of California,
10833 Le Conte Avenue, 11-934 Factor Building, Los Angeles,
California 90095, USA
Correspondence should be addressed to Charles L. Sawyers csawyers@med1.medsch.ucla.eduProstate 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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