HER2/ErbB2 Receptor Signaling in Rat and Human Prolactinoma Cells: Strategy for Targeted Prolactinoma Therapy

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/ErbB...

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Bibliographic Details
Published in:Molecular endocrinology (Baltimore, Md.) Md.), 2011-01, Vol.25 (1), p.92-103
Main Authors: Fukuoka, Hidenori, Cooper, Odelia, Mizutani, Jun, Tong, Yunguang, Ren, Song-Guang, Bannykh, Serguei, Melmed, Shlomo
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Cell Proliferation - drug effects
Female
Gene Expression Regulation, Neoplastic - drug effects
Humans
Lactotrophs - drug effects
Lactotrophs - metabolism
Lactotrophs - pathology
Molecular Targeted Therapy - methods
Prolactin - genetics
Prolactin - secretion
Prolactinoma - genetics
Prolactinoma - metabolism
Prolactinoma - secretion
Prolactinoma - therapy
Quinazolines - pharmacology
Rats
Receptor, ErbB-2 - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
Signal Transduction - drug effects
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Summary: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. This study demonstrates a role for functional HER2/ErbB2 in lactotroph adenoma and a strategy for novel targeted therapy of lapatinib in prolactinoma.
ISSN:0888-8809
1944-9917
DOI:10.1210/me.2010-0353