Rat prolactinoma cell growth regulation by epidermal growth factor receptor ligands

• Published in: Cancer research (Chicago, Ill.) Ill.), 2008-08, Vol.68 (15), p.6377-6386
• Main Authors: Vlotides, George, Siegel, Emily, Donangelo, Ines, Gutman, Shiri, Ren, Song-Guang, Melmed, Shlomo
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Base Sequence; Blotting, Western; Cell Division; Cell Line, Tumor; Cell Proliferation - drug effects; DNA Primers; Female; Flow Cytometry; Gene Expression - drug effects; Immunoprecipitation; Ligands; Mice; Mice, Nude; Pituitary Neoplasms - metabolism; Pituitary Neoplasms - pathology; Polymerase Chain Reaction; Prolactinoma - metabolism; Prolactinoma - pathology; Quinazolines - pharmacology; Rats; Receptor, Epidermal Growth Factor - metabolism
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-0508

Epidermal growth factor (EGF) regulates pituitary development, hormone synthesis, and cell proliferation. Although ErbB receptor family members are expressed in pituitary tumors, the effects of EGF signaling on pituitary tumors are not known. Immunoprecipitation and Western blot confirmed EGF receptor (EGFR) and p185(c-neu) protein expression in GH3 lacto-somatotroph but not in adrenocorticotropic hormone-secreting AtT20 pituitary tumor cells. EGF (5 nmol/L) selectively enhanced baseline ( approximately 4-fold) and serum-induced (>6-fold) prolactin (PRL) mRNA levels, whereas gefitinib, an EGFR antagonist, suppressed serum-induced cell proliferation and Pttg1 expression, blocked PRL gene expression, and reversed EGF-mediated somatotroph-lactotroph phenotype switching. Downstream EGFR signaling by ERK, but not phosphoinositide-3-kinase or protein kinase C, mediated the gefitinib response. Tumors in athymic mice implanted s.c. with GH3 cells resulted in weight gain accompanied by increased serum PRL, growth hormone, and insulin growth factor 1. Gefitinib decreased tumor volumes and peripheral hormone levels by approximately 30% and restored normal mouse body weight patterns. Mice treated with gefitinib exhibited decreased tumor tissue ERK1/2 phosphorylation and down-regulated tumor PRL and Pttg1 mRNA abundance. These results show that EGFR inhibition controls tumor growth and PRL secretion in experimental lacto-somatotroph tumors. EGFR inhibitors could therefore be useful for the control of PRL secretion and tumor load in prolactinomas resistant to dopaminergic treatment, or for those prolactinomas undergoing rare malignant transformation.