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Departments of 1 Urology and Surgery, Urological Diseases Research Center, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts and 2 Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, Louisiana
Requests for reprints: Michael R. Freeman, Children's Hospital Boston, Harvard Medical School, Enders Room 1161, 300 Longwood Avenue, Boston, MA 02115. Phone: 617-355-6054; Fax: 617-730-0238; E-mail: michael.freeman{at}childrens.harvard.edu.
Heparin-binding epidermal growth factor-like growth factor (HB-EGF), an ErbB1 ligand and prostate stromal growth factor, is an antagonist of androgen receptor (AR) function. In the LNCaP prostate cancer model, HB-EGF reduced AR protein levels and AR transactivation without affecting AR mRNA level or protein turnover. The signal to attenuate AR was mediated by the mammalian target of rapamycin, as shown by genetic and pharmacologic methods, and was independent of ErbB2/HER-2, extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase pathways. Additional evidence suggests that AR protein levels are highly sensitive to regulation by cap-dependent mRNA translation. These findings reveal a novel mechanism for regulation of AR by a classic growth factor system and indicate that a rapamycin-sensitive post-transcriptional pathway can attenuate or possibly bypass AR-mediated signaling.
Key Words: ErbB1/EGFR • phosphoinositide-3-kinase (PI3K) • Akt/protein kinase B (PKB) • rapamycin • S6 kinase (S6K1) • prostate cancer
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