Abstract
Characterizing mechanisms regulating mammary cell growth and differentiation is vital, as they may contribute to breast carcinogenesis. Here, we examine a cross talk mechanism(s) downstream of prolactin (PRL), a primary differentiation hormone, and epidermal growth factor (EGF), an important proliferative factor, in mammary epithelial cell growth and differentiation. Our data indicate that EGF exerts inhibitory effects on PRL-induced cellular differentiation by interfering with Stat5a-mediated gene expression independent of the PRL-proximal signaling cascade. Additionally, our data show that PRL is a potent inhibitor of EGF-induced cell proliferation. We identify tyrosine phosphorylation of the growth factor receptor-bound protein 2 (Grb2) as a critical mechanism by which PRL antagonizes EGF-induced cell proliferation by attenuating the activation of the Ras/mitogen-activated protein kinase (MAPK) pathway. Together, our results define a novel negative cross-regulation between PRL and EGF involving the Jak2/Stat5a and Ras/MAPK pathways through tyrosine phosphorylation of Grb2.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Breast Neoplasms / metabolism
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Cell Communication / physiology
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Cell Differentiation / physiology*
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Cell Line
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Cell Proliferation
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Enzyme Activation
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Epidermal Growth Factor / metabolism*
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Epithelial Cells / cytology
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Epithelial Cells / physiology*
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Extracellular Signal-Regulated MAP Kinases
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Female
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GRB2 Adaptor Protein / genetics
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GRB2 Adaptor Protein / metabolism*
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Humans
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Janus Kinase 2 / genetics
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Janus Kinase 2 / metabolism
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MAP Kinase Signaling System / physiology*
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Mammary Glands, Human / cytology*
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Mammary Glands, Human / physiology
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Phosphorylation
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Prolactin / metabolism*
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Tyrosine / metabolism
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ras Proteins / genetics
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ras Proteins / metabolism
Substances
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GRB2 Adaptor Protein
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STAT5 Transcription Factor
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STAT5A protein, human
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Tumor Suppressor Proteins
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Tyrosine
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Epidermal Growth Factor
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Prolactin
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JAK2 protein, human
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Janus Kinase 2
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Extracellular Signal-Regulated MAP Kinases
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ras Proteins