Abstract
Given the role of the EGFR/HER2 family of tyrosine kinases in breast cancer, we dissected the molecular basis of EGFR/HER2 kinase signaling in prostate cancer. Using the small molecule dual EGFR/HER2 inhibitor PKI-166, we show that the biologic effects of EGFR/HER-2 pathway inhibition are caused by reduced AR transcriptional activity. Additional genetic and pharmacologic experiments show that this modulation of AR function is mediated by the HER2/ERBB3 pathway, not by EGFR. This HER2/ERBB3 signal stabilizes AR protein levels and optimizes binding of AR to promoter/enhancer regions of androgen-regulated genes. Surprisingly, the downstream signaling pathway responsible for these effects appears to involve kinases other than Akt. These data suggest that the HER2/ERBB3 pathway is a critical target in hormone-refractory prostate cancer.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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COS Cells
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Chlorocebus aethiops
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DNA, Neoplasm / metabolism
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ErbB Receptors / physiology
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Humans
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Male
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Prostatic Neoplasms / metabolism*
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Protein Serine-Threonine Kinases / physiology
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-akt
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Pyrimidines / pharmacology*
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Pyrroles / pharmacology*
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RNA, Small Interfering / pharmacology
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Receptor, ErbB-2 / antagonists & inhibitors
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Receptor, ErbB-2 / physiology*
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Receptors, Androgen / metabolism*
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Signal Transduction
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Transfection
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Tumor Cells, Cultured
Substances
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DNA, Neoplasm
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Proto-Oncogene Proteins
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Pyrimidines
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Pyrroles
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RNA, Small Interfering
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Receptors, Androgen
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PKI 166
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ErbB Receptors
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Receptor, ErbB-2
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt