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Heregulin Regulates Prolactinoma Gene Expression

¹ Department of Medicine, Cedars-Sinai Medical Center, University of California School of Medicine, Los Angeles, California and ² Institute of Endocrinology, Metabolism, and Hypertension, Tel Aviv-Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv, Israel

Requests for reprints: Shlomo Melmed, Academic Affairs, Room 2015, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048. Phone: 310-423-4691; Fax: 310-423-0119; E-mail: melmed{at}csmc.edu.

Key Words: Pituitary tumor • Prolactinoma • GH4C1 cells • PRL • heregulin • p185^c-neu • ErbB3

To investigate the role of p185^her2/neu/ErbB3 signaling in pituitary tumor function, we examined these receptors in human prolactinomas. Immunofluorescent p185^her2/neu was detected in almost all (seven of eight), and ErbB3 expression in a subset (four of eight) of tumors (seven adenomas and one carcinoma). Quantitative PCR also showed abundant ErbB3 mRNA in tumor specimens derived from a rarely encountered prolactin-cell carcinoma. Activation of p185^c-neu/ErbB3 signaling with heregulin, the ErbB3 ligand, in rat lacto-somatotroph (GH4C1) tumor cells specifically induced prolactin (PRL) mRNA expression 5-fold and PRL secretion 4-fold, whereas growth hormone expression was unchanged. Heregulin (6 nmol/L) induced tyrosine phosphorylation and ErbB3 and p185^c-neu heterodimerization, with subsequent activation of intracellular ERK and Akt. The Akt signal was specific to ErbB3 activation by heregulin, and was not observed in response to epidermal growth factor activation of epidermal growth factor receptor. Gefitinib, the tyrosine kinase inhibitor, suppressed heregulin-mediated p185^c-neu/ErbB3 signaling to PRL. Heregulin induction of PRL was also abrogated by transfecting cells with short interfering RNA directed against ErbB3. Pharmacologic inhibition of heregulin-induced phosphoinositide-3-kinase/Akt (with LY294002) and ERK (with U0126) signaling, as well as short interfering RNA–mediated mitogen-activated protein kinase-1 down-regulation, showed ERK signaling as the primary transducer of heregulin signaling to PRL. These results show ErbB3 expression in human prolactinomas and a novel ErbB3-mediated mechanism for PRL regulation in experimental lactotroph tumors. Targeted inhibition of up-regulated p185^c-neu/ErbB3 activity could be useful for the treatment of aggressive prolactinomas resistant to conventional therapy. [Cancer Res 2009;69(10):4209–16]