Increase in amphiregulin and epiregulin in prostate cancer xenograft after androgen deprivation-impact of specific HER1 inhibition.
BACKGROUND
We investigated the expression of the epidermal growth factor (EGF) network before and after castration in the prostate cancer xenograft CWR22 implanted in nude mice, and examined the effects of gefitinib (Iresssa, ZD1839), a new drug directed towards the EGF tyrosine kinase receptor (HER1) of the EGF network.


METHODS
CWR22 prostate cancer xenografts were propagated in immunodeficient male mice. The expression of the growth factors and receptors in the EGF network was examined by real-time PCR analysis and ELISA at 0, 7, 14, and 30 days after castration, and the tumor growth was examined after treatment with gefitinib or placebo.


RESULTS
A fraction of growth factors showed a steady increase in the mRNA expression reaching between fourfold and eightfold 30 days after castration, including amphiregulin (P < 0.005) and epiregulin (P < 0.001). ELISA for amphiregulin showed a fivefold increase 30 days after castration. Tumor bearing mice were castrated and treated with or without the HER1 tyrosine kinase inhibitor gefitinib. Tumor involution was significantly increased by castration plus gefitinib as compared to castration alone.


CONCLUSIONS
Castration leads to adaptive increase in the concentrations of a subset of growth factors from the EGF network in the androgen sensitive CWR22 prostate cancer xenograft. Specific inhibition of the HER1 tyrosine kinase receptor significantly increases the tumor involution, and suggests that HER1 targeted drugs could be of therapeutic relevance in the treatment of advanced prostate cancer.
Tørring
Niels
N
Molecular Diagnostics Laboratory, Department of Clinical Biochemistry-AKH, Aarhus University Hospital, Aarhus C, Denmark. nto@ki.au.dk
Hansen
Frederik Dagnaes
FD
Sørensen
Boe Sandahl
BS
Ørntoft
Torben F
TF
Nexø
Ebba
E
D066258:Amphiregulin; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000235:genetics* / Q000378:metabolism; D066260:Epiregulin; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D015870:Gene Expression / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D066258:Amphiregulin; D000728:Androgens; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D066260:Epiregulin; C587881:Ereg protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000077156:Gefitinib