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Heregulin Co-opts PR Transcriptional Action Via Stat3 Role As a Coregulator to Drive Cancer Growth
- Publication Year :
- 2015
- Publisher :
- Endocrine Society, 2015.
-
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 p21CIP1 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, p21CIP1, 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.
- Subjects :
- Cyclin-Dependent Kinase Inhibitor p21
STAT3 Transcription Factor
Transcriptional Activation
Receptor, ErbB-2
Neuregulin-1
Molecular Sequence Data
bcl-X Protein
Breast Neoplasms
Receptor tyrosine kinase
Endocrinology
Mammary tumor virus
Progesterone receptor
Coactivator
Animals
Promoter Regions, Genetic
Molecular Biology
Original Research
Cell Proliferation
Cell Nucleus
Mice, Inbred BALB C
Binding Sites
biology
Base Sequence
Mouse mammary tumor virus
General Medicine
biology.organism_classification
Gene Expression Regulation, Neoplastic
Mammary Tumor Virus, Mouse
biology.protein
Cancer research
Neuregulin
Female
Signal transduction
Receptors, Progesterone
Protein Binding
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....29bda64177cc7f7c7433116266ace5c0