title: HER2/ErbB2 receptor signaling in rat and human prolactinoma cells: strategy for targeted prolactinoma therapy.
abstract: Dopamine agonist resistance or intolerance is encountered in approximately 20% of prolactinoma patients. Because human epidermal growth factor receptor 2 (HER2)/ErbB2 is overexpressed in prolactinomas and ErbB receptor ligands regulate prolactin (PRL) gene expression, we tested the role of HER2/ErbB2 in prolactinoma hormone regulation and adenoma cell proliferation to assess the rationale for targeting this receptor for prolactinoma therapy. As we showed prolactinoma HER2 overexpression, we generated constitutively active HER2-stable GH3 cell transfectants (HER2CA). PRL mRNA levels were induced approximately 250-fold and PRL secretion was enhanced 100-fold in HER2CA cells, which also exhibited increased proliferation. Lapatinib, a dual tyrosine kinase inhibitor (TKI) of both epidermal growth factor receptor (EGFR)/ErbB1 and HER2, blocked receptor signaling, and suppressed PRL expression more than gefitinib, a TKI of EGFR/ErbB1. Lapatinib also suppressed colony formation in soft agar more than gefitinib. Oral lapatinib treatment caused tumor shrinkage and serum PRL suppression both in HER2CA transfectant-inoculated Wistar-Furth rats and in estrogen-induced Fischer344 rat prolactinomas. In cultured human cells derived from resected prolactinoma tissue, lapatinib suppressed both PRL mRNA expression and secretion. These results demonstrate that prolactinoma HER2 potently induces PRL and regulates experimental prolactinoma cell proliferation. Because pituitary HER2 signaling is abrogated by TKIs, this receptor could be an effective target for prolactinoma therapy.
authors.affiliation: Cedars-Sinai Medical Center, Department of Academic Affairs, 8700 Beverly Boulevard Plaza North, Los Angeles, CA 90048, USA.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Fukuoka
authors.forename: Odelia
authors.initials: O
authors.lastname: Cooper
authors.forename: Jun
authors.initials: J
authors.lastname: Mizutani
authors.forename: Yunguang
authors.initials: Y
authors.lastname: Tong
authors.forename: Song-Guang
authors.initials: SG
authors.lastname: Ren
authors.forename: Serguei
authors.initials: S
authors.lastname: Bannykh
authors.forename: Shlomo
authors.initials: S
authors.lastname: Melmed
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D052682:Lactotrophs / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077341:Lapatinib; D058990:Molecular Targeted Therapy / Q000379:methods*; D011388:Prolactin / Q000235:genetics / Q000378:metabolism; D015175:Prolactinoma / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000077156:Gefitinib; D000077341:Lapatinib; D011388:Prolactin; D011799:Quinazolines; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases