ErbB receptor-driven prolactinomas respond to targeted lapatinib treatment in female transgenic mice.
As ErbB receptors are expressed in prolactinomas and exhibit downstream effects on prolactin (PRL) production and cell proliferation, we generated transgenic mice using a PRL enhancer/promoter expression system to restrict lactotroph-specific expression of human epidermal growth factor receptor (EGFR) or human EGFR2 (HER2). EGFR or HER2 transgenic mice developed prolactinomas between 13 and 15 months, and confocal immunofluorescence and Western blot analysis confirmed lactotroph-restricted PRL and EGFR or HER2 coexpression. Circulating PRL levels in EGFR and HER2 transgenic mice were increased 5- and 3.8-fold, respectively. Inhibiting EGFR or HER2 signaling with oral lapatinib (100 mg/kg), a dual tyrosine kinase inhibitor for both EGFR and HER2, suppressed circulating PRL by 72% and attenuated tumor PRL expression by 80% and also attenuated downstream tumor EGFR/HER2 signaling. This model demonstrates the role of ErbB receptors underlying prolactinoma tumorigenesis and the feasibility of targeting these receptors for translation to treatment of refractory prolactinomas.
Pituitary Center, Department of Medicine (X.L., M.K., T.A., O.C., H.F., S.M.) and Research Division of Immunology, Department of Biomedical Sciences (Y.T., M.T.), Cedars-Sinai Medical Center, Los Angeles, California 90048.
Xiaohai
X
Liu
Maya
M
Kano
Takako
T
Araki
Odelia
O
Cooper
Hidenori
H
Fukuoka
Yukiko
Y
Tone
Masahide
M
Tone
Shlomo
S
Melmed
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004742:Enhancer Elements, Genetic; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D008822:Mice, Transgenic; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015175:Prolactinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011799:Quinazolines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D011799:Quinazolines; D000077341:Lapatinib; C512478:EGFR protein, human; D066246:ErbB Receptors