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Androgen-Dependent Regulation of Her-2/neu in Prostate Cancer Cells

¹ Department of Medical Oncology, Dana-Farber Cancer Institute; Departments of ² Medicine and ³ Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and ⁴ Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts

Requests for reprints: Massimo Loda, or William C. Hahn, Department of Medical Oncology, Dana-Farber Cancer Institute, D1536, 44 Binney Street, Boston, MA 02115. Phone: 617-632-4001; Fax: 617-632-4005; E-mail: massimo_loda{at}dfci.harvard.edu or william_hahn{at}dfci.harvard.edu.

The mechanisms underlying the progression of prostate cancer to a state of resistance to hormone ablation remain poorly understood. Here, we have investigated the relationship between androgen receptor (AR) and Her-2/neu in prostate cancer cells. Overexpression of Her-2/neu (c-ErbB2) activates the AR pathway and confers a survival and growth advantage to prostate cancer cells in an androgen-deficient milieu. In vitro, the absence of androgens or AR blockade induced Her-2/neu protein expression and phosphorylation. In contrast, upon readministration of androgens, Her-2/neu mRNA, protein, and phosphorylation levels decreased linearly with increasing concentrations of dihydrotestosterone as LNCaP cells reentered the cell cycle. In vivo, induction of Her-2/neu by castration in orthotopically injected LNCaP cells resulted in a progressive increase in prostate-specific antigen secretion into the mouse serum, indicating that Her-2/neu-mediated, AR-dependent transcription occurs following castration and results in tumor cell growth. Finally, selection of LNCaP cells stably transfected with short hairpin RNA specific for AR resulted in Her-2/neu overexpression. Similarly, knockdown of Her-2/neu led to induction of AR. However, when Her-2/neu and AR were simultaneously targeted, we observed cell death, whereas surviving cells retained low level expression of Her-2/neu. Thus, induction and activation of Her-2/neu occurs in an androgen-depleted environment or as a result of AR inactivation, promoting ablation-resistant survival of prostate cancer cells. These data provide the biochemical rationale to target Her-2/neu in hormone-refractory prostate cancer. (Cancer Res 2006; 66(11): 5723-8)

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