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Exon-Level Microarray Analyses Identify Alternative Splicing Programs in Breast Cancer

Lapuk, Anna and Marr, Henry and Jakkula, Lakshmi and Pedro, Helder and Bhattacharya, Sanchita and Purdom, Elizabeth and Hu, Zhi and Simpson, Ken and Pachter, Lior and Durinck, Steffen and Wang, Nicholas and Parvin, Bahram and Fontenay, Gerald and Speed, Terence and Garbe, James and Stampfer, Martha and Bayandorian, Hovig and Dorton, Shannon and Clark, Tyson A. and Schweitzer, Anthony and Wyrobek, Andrew and Feiler, Heidi and Spellman, Paul and Conboy, John and Gray, Joe W. (2010) Exon-Level Microarray Analyses Identify Alternative Splicing Programs in Breast Cancer. Molecular Cancer Research, 8 (7). pp. 961-974. ISSN 1541-7786. PMCID PMC2911965. doi:10.1158/1541-7786.MCR-09-0528.

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Protein isoforms produced by alternative splicing (AS) of many genes have been implicated in several aspects of cancer genesis and progression. These observations motivated a genome-wide assessment of AS in breast cancer. We accomplished this by measuring exon level expression in 31 breast cancer and nonmalignant immortalized cell lines representing luminal, basal, and claudin-low breast cancer subtypes using Affymetrix Human Junction Arrays. We analyzed these data using a computational pipeline specifically designed to detect AS with a low false-positive rate. This identified 181 splice events representing 156 genes as candidates for AS. Reverse transcription-PCR validation of a subset of predicted AS events confirmed 90%. Approximately half of the AS events were associated with basal, luminal, or claudin-low breast cancer subtypes. Exons involved in claudin-low subtype–specific AS were significantly associated with the presence of evolutionarily conserved binding motifs for the tissue-specific Fox2 splicing factor. Small interfering RNA knockdown of Fox2 confirmed the involvement of this splicing factor in subtype-specific AS. The subtype-specific AS detected in this study likely reflects the splicing pattern in the breast cancer progenitor cells in which the tumor arose and suggests the utility of assays for Fox-mediated AS in cancer subtype definition and early detection. These data also suggest the possibility of reducing the toxicity of protein-targeted breast cancer treatments by targeting protein isoforms that are not present in limiting normal tissues.

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Pachter, Lior0000-0002-9164-6231
Additional Information:© 2010 American Association for Cancer Research. Received 12/07/2009; revised 05/21/2010; accepted 06/01/2010; published OnlineFirst 07/06/2010. Grant Support: Director, Office of Science, Office of Biological & Environmental Research, of the U.S. Department of Energy under contract no. DE-AC02-05CH11231, USAMRMC W81XWH-07-1-0663 and NIH grants CA58207, CA112970, and CA 126477 (J.G. Conboy) by NIH grant HL045182 (J.W. Gray); and by the FCT SFRH/BD 33203 2007 (H. Pedro). Disclosure of Potential Conflicts of Interest: J.W. Gray received early access to microarrays from Affymetrix. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Funding AgencyGrant Number
Department of Energy (DOE)DE-AC02-05CH11231
US Army Medical Research and Materiel Command (USAMRMC)W81XWH-07-1-0663
Fundação para a Ciência e a Tecnologia (FCT)SFRH/BD 33203 2007
Issue or Number:7
PubMed Central ID:PMC2911965
Record Number:CaltechAUTHORS:20170306-123614363
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Official Citation:Exon-Level Microarray Analyses Identify Alternative Splicing Programs in Breast Cancer Anna Lapuk, Henry Marr, Lakshmi Jakkula, Helder Pedro, Sanchita Bhattacharya, Elizabeth Purdom, Zhi Hu, Ken Simpson, Lior Pachter, Steffen Durinck, Nicholas Wang, Bahram Parvin, Gerald Fontenay, Terence Speed, James Garbe, Martha Stampfer, Hovig Bayandorian, Shannon Dorton, Tyson A. Clark, Anthony Schweitzer, Andrew Wyrobek, Heidi Feiler, Paul Spellman, John Conboy and Joe W. Gray Mol Cancer Res July 6 2010 DOI: 10.1158/1541-7786.MCR-09-0528
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74791
Deposited By: George Porter
Deposited On:06 Mar 2017 21:33
Last Modified:11 Nov 2021 05:29

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