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Sci Signal ; 6(282): ra53, 2013 Jul 02.
Article in English | MEDLINE | ID: mdl-23821771

ABSTRACT

Hormonal stress response is associated with the pathogenesis of disease, including cancer. The role of the stress hormone CRH (corticotropin-releasing hormone) in breast cancer is complex, and its abundance and biological activity may be modulated by estrogen. In the estrogen receptor-positive (ER+) malignant mammary epithelial cell line MCF7, CRH activated numerous kinases and downstream effectors, at least some of which were mediated by the CRH receptor type 1 (CRH-R1). CRH also increased the transcription of many genes that encode effectors, transcriptional targets, or regulators associated with estrogen signaling. Estrogen increased the abundance of the mRNA encoding CRH-R2 and an alternative splice variant encoding CRH-R1 in which exon 12 was deleted [CRH-R1(Δ12)]. Estrogen inhibited the expression SRSF6, which encodes serine/arginine-rich splicing factor 55 (SRp55). An increase in CRH-R1(Δ12), in response to either estrogen or SRp55 knockdown, dampened the cellular response to CRH and prevented its inhibitory effects on cell invasion. SRp55 knockdown also induced additional splicing events within exons 9 to 12 of CRH-R1, whereas overexpression of SRp55 prevented estrogen-induced generation of CRH-R1(Δ12). ER+ breast tumors had increased CRH-R2 and CRH-R1(Δ12) mRNA abundance, which was associated with decreased abundance of the mRNA encoding SRp55, compared with the amounts in ER- tumors, suggesting that estrogen contributes to the pathophysiology of ER+ breast cancer by altering CRH receptor diversity and disrupting CRH-mediated signaling.


Subject(s)
Alternative Splicing/drug effects , Breast Neoplasms/genetics , Estrogens/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Receptors, Corticotropin-Releasing Hormone/genetics , Blotting, Western , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Movement/drug effects , Cell Movement/genetics , Corticotropin-Releasing Hormone/pharmacology , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Humans , MCF-7 Cells , Microscopy, Confocal , Mitogen-Activated Protein Kinases/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Phosphoproteins/genetics , Phosphoproteins/metabolism , Phosphorylation/drug effects , RNA Interference , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Receptors, Corticotropin-Releasing Hormone/metabolism , Receptors, Estrogen/genetics , Receptors, Estrogen/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Serine-Arginine Splicing Factors , Signal Transduction/drug effects , Signal Transduction/genetics
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