Abstract
Progesterone receptor (PR) and ErbB-2 bidirectional cross talk participates in breast cancer development. Here, we identified a new mechanism of the PR and ErbB-2 interaction involving the PR induction of ErbB-2 nuclear translocation and the assembly of a transcriptional complex in which ErbB-2 acts as a coactivator of Stat3. We also highlighted that the function of ErbB-2 as a Stat3 coactivator drives progestin-induced cyclin D1 promoter activation. Notably, PR is also recruited together with Stat3 and ErbB-2 to the cyclin D1 promoter, unraveling a new and unexpected nonclassical PR genomic mechanism. The assembly of the nuclear Stat3/ErbB-2 transcriptional complex plays a key role in the proliferation of breast tumors with functional PR and ErbB-2. Our findings reveal a novel therapeutic intervention for PR- and ErbB-2-positive breast tumors via the specific blockage of ErbB-2 nuclear translocation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Animals
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Base Sequence
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Breast Neoplasms / etiology*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cell Proliferation
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Female
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Gene Knockdown Techniques
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Genes, bcl-1
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Humans
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Mammary Neoplasms, Experimental / etiology*
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / metabolism*
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Mammary Neoplasms, Experimental / pathology
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Medroxyprogesterone Acetate / toxicity
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Mice
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Mice, Inbred BALB C
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Progestins / toxicity
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Promoter Regions, Genetic
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RNA, Small Interfering / genetics
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Receptor, ErbB-2 / antagonists & inhibitors
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism*
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Receptors, Progesterone / antagonists & inhibitors
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Receptors, Progesterone / genetics
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Receptors, Progesterone / metabolism*
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STAT3 Transcription Factor / antagonists & inhibitors
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism*
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Signal Transduction
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Trans-Activators / metabolism*
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Transcription, Genetic / drug effects
Substances
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Progestins
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RNA, Small Interfering
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Receptors, Progesterone
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STAT3 Transcription Factor
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Stat3 protein, mouse
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Trans-Activators
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Medroxyprogesterone Acetate
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Erbb2 protein, mouse
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Receptor, ErbB-2