Title | Androgen-dependent regulation of Her-2/neu in prostate cancer cells. |
Publication Type | Journal Article |
Year of Publication | 2006 |
Authors | Berger R, Lin DI, Nieto M, Sicinska E, Garraway LA, Adams H, Signoretti S, Hahn WC, Loda M |
Journal | Cancer Res |
Volume | 66 |
Issue | 11 |
Pagination | 5723-8 |
Date Published | 2006 Jun 01 |
ISSN | 0008-5472 |
Keywords | Androgen Receptor Antagonists, Androgens, Animals, Cell Growth Processes, Cell Line, Tumor, Dihydrotestosterone, Humans, Male, Mice, Neoplasms, Hormone-Dependent, Phosphorylation, Prostatic Neoplasms, Receptor, ErbB-2, Receptors, Androgen, RNA, Messenger, RNA, Small Interfering, Transfection |
Abstract | 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. |
DOI | 10.1158/0008-5472.CAN-05-3928 |
Alternate Journal | Cancer Res |
PubMed ID | 16740710 |
Grant List | T32 CA009172 / CA / NCI NIH HHS / United States 5P50CA90381 / CA / NCI NIH HHS / United States P01 CA089021 / CA / NCI NIH HHS / United States |
Related Faculty:
Massimo Loda, M.D.