Heregulin regulates prolactinoma gene expression

George Vlotides, Odelia Cooper, Yen Hao Chen, Song Guang Ren, Yona Greenman, Shlomo Melmed

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

To investigate the role of p185her2/neu/ErbB3 signaling in pituitary tumor function, we examined these receptors in human prolactinomas. Immunofluorescent p185her2/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 p185c-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 p185c-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 p185c-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 p185c-neu/ErbB3 activity could be useful for the treatment of aggressive prolactinomas resistant to conventional therapy.

Original languageEnglish (US)
Pages (from-to)4209-4216
Number of pages8
JournalCancer Research
Volume69
Issue number10
DOIs
StatePublished - May 15 2009

Fingerprint

Neuregulin-1
Prolactinoma
Prolactin
Gene Expression
Small Interfering RNA
Neoplasms
Lactotrophs
Somatotrophs
Carcinoma
Messenger RNA
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
1-Phosphatidylinositol 4-Kinase
Mitogen-Activated Protein Kinase 1
Pituitary Neoplasms
Transducers
Epidermal Growth Factor Receptor
Epidermal Growth Factor
Adenoma
Protein-Tyrosine Kinases
Growth Hormone

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Vlotides, G., Cooper, O., Chen, Y. H., Ren, S. G., Greenman, Y., & Melmed, S. (2009). Heregulin regulates prolactinoma gene expression. Cancer Research, 69(10), 4209-4216. https://doi.org/10.1158/0008-5472.CAN-08-4934

Heregulin regulates prolactinoma gene expression. / Vlotides, George; Cooper, Odelia; Chen, Yen Hao; Ren, Song Guang; Greenman, Yona; Melmed, Shlomo.

In: Cancer Research, Vol. 69, No. 10, 15.05.2009, p. 4209-4216.

Research output: Contribution to journalArticle

Vlotides, G, Cooper, O, Chen, YH, Ren, SG, Greenman, Y & Melmed, S 2009, 'Heregulin regulates prolactinoma gene expression', Cancer Research, vol. 69, no. 10, pp. 4209-4216. https://doi.org/10.1158/0008-5472.CAN-08-4934
Vlotides G, Cooper O, Chen YH, Ren SG, Greenman Y, Melmed S. Heregulin regulates prolactinoma gene expression. Cancer Research. 2009 May 15;69(10):4209-4216. https://doi.org/10.1158/0008-5472.CAN-08-4934
Vlotides, George ; Cooper, Odelia ; Chen, Yen Hao ; Ren, Song Guang ; Greenman, Yona ; Melmed, Shlomo. / Heregulin regulates prolactinoma gene expression. In: Cancer Research. 2009 ; Vol. 69, No. 10. pp. 4209-4216.
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