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Estrogen Alters the Splicing of Type 1 Corticotropin-Releasing Hormone Receptor in Breast Cancer Cells

Lal, Suchita and Allan, Anna and Markovic, Danijela and Walker, Rosemary and Macartney, James and Europe-Finner, Nick and Tyson-Capper, Alison and Grammatopoulos, Dimitris K. (2013) Estrogen Alters the Splicing of Type 1 Corticotropin-Releasing Hormone Receptor in Breast Cancer Cells. Science Signaling, 6 (282). Art. No. ra53. ISSN 1945-0877. doi:10.1126/scisignal.2003926.

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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.

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Additional Information:© 2013 American Association for the Advancement of Science. Submitted 26 December 2012; Accepted 11 June 2013; Final Publication 2 July 2013. We would like to thank S. Stranges and K. Ngianga-Bakwin, Warwick Medical School, for expert statistical guidance and support. Funding: Research was supported by a Pathological Society of Great Britain and Ireland pilot grant and undergraduate Bursary and a Wellcome Trust undergraduate vacation scholarship and by the Birmingham-Warwick Science City Research Alliance. Author contributions: S.L., A.A., and D.M. performed the experiments and data analysis; R.W. and A.T.-C. provided materials and reagents and contributed to data analysis and manuscript writing; N.E.-F., J.M., and D.K.G. contributed to the design of the study, data interpretation, and manuscript writing. Competing interests: The authors declare that they have no competing interests. Data and materials availability: The PCR array data have been deposited in the Gene Expression Omnibus (http://www. functional genomics data repository, accession number GSE47958.
Funding AgencyGrant Number
Pathological Society of Great BritainUNSPECIFIED
Ireland pilot grant and undergraduate BursaryUNSPECIFIED
Wellcome Trust undergraduate vacation scholarshipUNSPECIFIED
Birmingham- Warwick Science City Research AllianceUNSPECIFIED
Issue or Number:282
Record Number:CaltechAUTHORS:20130808-104729171
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Official Citation:S. Lal, A. Allan, D. Markovic, R. Walker, J. Macartney, N. Europe-Finner, A. Tyson-Capper, D. K. Grammatopoulos, Estrogen Alters the Splicing of Type 1 Corticotropin-Releasing Hormone Receptor in Breast Cancer Cells. Sci. Signal. 6, ra53 (2013).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:39818
Deposited On:09 Aug 2013 16:37
Last Modified:09 Nov 2021 23:47

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