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.