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Abnormal Proliferation02:23

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Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
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Modified Yeast-Two-Hybrid System to Identify Proteins Interacting with the Growth Factor Progranulin
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Heregulin regulates prolactinoma gene expression.

George Vlotides1, Odelia Cooper, Yen-Hao Chen

  • 1Department of Medicine, Cedars-Sinai Medical Center, University of California School of Medicine, Los Angeles, CA, USA.

Cancer Research
|April 30, 2009
PubMed
Summary

The p185(her2/neu)/ErbB3 signaling pathway regulates prolactin in pituitary tumors. Targeting this pathway may offer new treatments for aggressive prolactinomas.

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Area of Science:

  • Endocrinology
  • Oncology
  • Molecular Biology

Background:

  • Pituitary tumors, particularly prolactinomas, can be aggressive and resistant to therapy.
  • The role of p185(her2/neu)/ErbB3 signaling in pituitary tumor function is not well understood.

Purpose of the Study:

  • To investigate the expression and function of p185(her2/neu)/ErbB3 signaling in human prolactinomas.
  • To elucidate the downstream signaling pathways involved in heregulin-induced prolactin regulation.

Main Methods:

  • Immunofluorescence and quantitative PCR to detect p185(her2/neu) and ErbB3 expression in human prolactinoma samples.
  • Stimulation of rat lacto-somatotroph (GH4C1) tumor cells with heregulin to assess prolactin (PRL) mRNA and secretion.
  • Analysis of intracellular signaling pathways (ERK, Akt) and heterodimerization using western blotting and RNA interference.
  • Pharmacological inhibition of signaling pathways with gefitinib, LY294002, and U0126.

Main Results:

  • p185(her2/neu) and ErbB3 were detected in human prolactinomas, including a prolactin-cell carcinoma.
  • Heregulin specifically induced PRL mRNA and secretion in GH4C1 cells.
  • Heregulin activated p185(c-neu)/ErbB3 signaling, leading to ERK and Akt activation.
  • Gefitinib and ErbB3-targeted siRNA suppressed heregulin-mediated PRL induction.
  • ERK signaling was identified as the primary transducer of heregulin signaling to PRL.

Conclusions:

  • ErbB3 is expressed in human prolactinomas and mediates PRL regulation in experimental lactotroph tumors.
  • Targeted inhibition of p185(her2/neu)/ErbB3 signaling presents a potential therapeutic strategy for aggressive prolactinomas.