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Estrogen alters the splicing of Type 1 corticotropin-releasing hormone receptor in breast cancer cells
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Lal, S., Allan, A., Markovic, D., Walker, R., MacArtney, J., Europe-Finner, N., Tyson-Capper, A. and Grammatopoulos, D. (2013) Estrogen alters the splicing of Type 1 corticotropin-releasing hormone receptor in breast cancer cells. Science Signaling, 6 (282). ra53. doi:10.1126/scisignal.2003926 ISSN 1945-0877.
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Official URL: http://dx.doi.org/10.1126/scisignal.2003926
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.
Item Type: | Journal Article | ||||
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Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Reproductive Health ( - until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Journal or Publication Title: | Science Signaling | ||||
Publisher: | American Association for the Advancement of Science | ||||
ISSN: | 1945-0877 | ||||
Official Date: | 2013 | ||||
Dates: |
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Volume: | 6 | ||||
Number: | 282 | ||||
Article Number: | ra53 | ||||
DOI: | 10.1126/scisignal.2003926 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access |
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