title: Inhibition of HER-2/neu kinase impairs androgen receptor recruitment to the androgen responsive enhancer.
abstract: Advanced prostate cancer invariably recurs despite androgen deprivation therapy. The androgen receptor (AR) likely plays a key role in this progression and in the continued survival and proliferation of prostate cancer cells in the low androgen environment. Cross-talk with growth factor receptors, such as epidermal growth factor receptor (EGFR) family, has been postulated as a potential mechanism to activate AR in recurrent prostate cancer. We have investigated the role of HER-2/neu (ErbB-2) tyrosine kinase in AR function by characterizing the effect of inhibiting endogenous HER-2 activity in LNCaP cells. We used two independent methods, expression of intracellular single-chain antibody against HER-2 and treatment with a novel dual EGFR/HER-2 kinase inhibitor GW572016 (lapatinib). Expression of intracellular HER-2 antibody scFv-5R and treatment with GW572016 inhibited HER-2 signaling. This HER-2 inhibition led to impairment of AR-mediated functions, such as androgen-stimulated growth and the induction of endogenous prostate-specific antigen (PSA) mRNA and protein. Androgen-stimulated recruitment of AR and histone acetylation at the androgen responsive enhancer of the PSA gene, detected by chromatin immunoprecipitation analysis, were impaired by HER-2 inhibition. GW572016 was more potent in its ability to inhibit PSA expression and AR recruitment and histone acetylation than the EGFR-selective kinase inhibitor ZD1839 (gefitinib), consistent with the HER-2 kinase playing the major role in AR regulation. These results show that HER-2 signaling is required for optimal transcriptional activity of AR in prostate cancer cells and suggest that HER-2 inhibition may provide a novel strategy to disrupt AR function in prostate cancer.
authors.affiliation: Lineberger Comprehensive Cancer Center, Department of Radiation Oncology, University of North Carolina, 102 Mason Farm Road, Chapel Hill, NC 27599, USA.
authors.forename: Yuanbo
authors.initials: Y
authors.lastname: Liu
authors.forename: Samarpan
authors.initials: S
authors.lastname: Majumder
authors.forename: Wesley
authors.initials: W
authors.lastname: McCall
authors.forename: Carolyn I
authors.initials: CI
authors.lastname: Sartor
authors.forename: James L
authors.initials: JL
authors.lastname: Mohler
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Gregory
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.forename: Young E
authors.initials: YE
authors.lastname: Whang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000502:physiology; D045744:Cell Line, Tumor; D002843:Chromatin / Q000187:drug effects / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D013196:Dihydrotestosterone / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000077156:Gefitinib; D006657:Histones / Q000378:metabolism; D006801:Humans; D007128:Immunoglobulin Fragments / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D000077341:Lapatinib; D008297:Male; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020218:Response Elements; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D002843:Chromatin; D013196:Dihydrotestosterone; D066246:ErbB Receptors; D000077156:Gefitinib; D006657:Histones; D007128:Immunoglobulin Fragments; D000077341:Lapatinib; D017430:Prostate-Specific Antigen; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen