title: Breast cancer cells proliferation is regulated by tyrosine phosphatase SHP1 through c-jun N-terminal kinase and cooperative induction of RFX-1 and AP-4 transcription factors.
abstract: In this study, we show that proliferation of breast cancer cells is suppressed by IGF-1-activated JNK MAPK pathway. The molecular mechanism by which c-jun-NH,-kinase (JNK) activation induces antiproliferative signals in IGF-1-stimulated breast cancer cells remains unknown. Tyrosine phosphatase SHP1 is known to negatively regulate signal transduction pathways activated by cell surface receptors including IGF-1. Moreover, SHP1 transcript and protein levels are increased in epithelial tumors. Therefore, we hypothesized that IGF-activated JNK induces expression of SHP1 in breast cancer cells. To further clarify the role of SHP1 in tumor growth, we correlated the proliferation rates of breast adenocarcinoma cells with SHP1 expression and JNK activation. We show that proliferation of serum- or IGF-1-stimulated breast adenocarcinoma cells is negatively regulated by SHP1 and show for the first time that IGF-1-activated JNK induces SHP1 expression in MCF-7 cells used as experimental model. In an attempt to understand the mechanism by which serum- or IGF-1-activated JNK induces SHP1 expression resulting in suppression of cell proliferation, we reveal for the first time that in serum- or IGF-1-stimulated breast cancer MCF-7 cells, JNK induces SHP1 expression through the binding of AP-4 and RFX-1 transcription factors to the epithelial tissue-specific SHP1 promoter. Overall, we show for the first time that IGF-1-stimulated proliferation of breast adenocarcinoma cells is negatively regulated by SHP1 through activation of JNK.
authors: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors: Shahreen
authors: S
authors: Amin
authors: Ashok
authors: A
authors: Kumar
authors: Ladan
authors: L
authors: Nilchi
authors: Kathryn
authors: K
authors: Wright
authors: Maya
authors: M
authors: Kozlowski
mesh_terms: D033964:Adaptor Protein Complex 4 / Q000235:genetics / Q000378:metabolism*; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D000071716:Regulatory Factor X1; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D033964:Adaptor Protein Complex 4; D004268:DNA-Binding Proteins; D005419:Flavonoids; C000605537:RFX1 protein, human; D000071701:Regulatory Factor X Transcription Factors; D000071716:Regulatory Factor X1; D014157:Transcription Factors; D007334:Insulin-Like Growth Factor I; D048031:JNK Mitogen-Activated Protein Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one