Abstract
Accumulated findings have demonstrated the presence of bidirectional interactions between progesterone receptor (PR) and the ErbB family of receptor tyrosine kinases signaling pathways in breast cancer. We previously revealed signal transducer and activator of transcription 3 (Stat3) as a nodal convergence point between said signaling pathways proving that Stat3 is activated by one of the ErbBs' ligands, heregulin (HRG)β1 via ErbB2 and through the co-option of PR as a signaling molecule. Here, we found that HRGβ1 induced Stat3 recruitment to the promoters of the progestin-regulated cell cycle modulators Bcl-XL and p21(CIP1) and also stimulated Stat3 binding to the mouse mammary tumor virus promoter, which carries consensus progesterone response elements. Interestingly, HRGβ1-activated Stat3 displayed differential functions on PR activity depending on the promoter bound. Indeed, Stat3 was required for PR binding in bcl-X, p21(CIP1), and c-myc promoters while exerting a PR coactivator function on the mouse mammary tumor virus promoter. Stat3 also proved to be necessary for HRGβ1-induced in vivo tumor growth. Our results endow Stat3 a novel function as a coregulator of HRGβ1-activated PR to promote breast cancer growth. These findings underscore the importance of understanding the complex interactions between PR and other regulatory factors, such as Stat3, that contribute to determine the context-dependent transcriptional actions of PR.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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Binding Sites
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Breast Neoplasms / genetics*
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Breast Neoplasms / pathology*
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cell Proliferation / drug effects
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Mammary Tumor Virus, Mouse / genetics
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Mice, Inbred BALB C
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Molecular Sequence Data
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Neuregulin-1 / pharmacology*
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Promoter Regions, Genetic
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Protein Binding / drug effects
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Receptor, ErbB-2 / metabolism
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Receptors, Progesterone / genetics*
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STAT3 Transcription Factor / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Transcriptional Activation / drug effects
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Transcriptional Activation / genetics*
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
Substances
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Cyclin-Dependent Kinase Inhibitor p21
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Neuregulin-1
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Receptors, Progesterone
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STAT3 Transcription Factor
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bcl-X Protein
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heregulin beta1
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ERBB2 protein, human
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Receptor, ErbB-2
Grants and funding
This work was supported by the Susan G. Komen for the Cure Investigator Initiated Research Grant KG090250, National Agency of Scientific Promotion of Argentina Grants PICT 2010 0122, PICT 2012 668, and PID 2012 0066, and the Argentina National Council of Scientific Research (CONICET) Grant PIP 737 (to P.V.E.); by the Oncomed-Reno CONICET Grant 1819/03 (to P.V.E. and R.S.); and by National Agency of Scientific Promotion of Argentina Grants PICT 2008 0189 and PICT 2012 1017 and the CONICET Grant PIP 059 (to C.J.P.).