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

Sci. Signal., 2 July 2013
Vol. 6, Issue 282, p. ra53
[DOI: 10.1126/scisignal.2003926]

Suchita Lal¹, Anna Allan¹, Danijela Markovic², Rosemary Walker³, James Macartney¹, Nick Europe-Finner⁴, Alison Tyson-Capper⁴, and Dimitris K. Grammatopoulos^1*

¹ Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
² Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
³ Department of Cancer Studies & Molecular Medicine, Clinical Sciences Building, University of Leicester, Leicester Royal Infirmary, Leicester LE2 7LX, UK.
⁴ Reproductive and Vascular Biology Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.

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(12)]. Estrogen inhibited the expression SRSF6, which encodes serine/arginine-rich splicing factor 55 (SRp55). An increase in CRH-R1(12), 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(12). ER⁺ breast tumors had increased CRH-R2 and CRH-R1(12) 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.

* Corresponding author. E-mail: d.grammatopoulos{at}warwick.ac.uk

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).

Source: http://stke.sciencemag.org/cgi/content/abstract/6/282/ra53?rss=1

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