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

Lapuk, A; Marr, H; Jakkula, L; Pedro, H; Bhattacharya, S; Purdom, E; Hu, Z; Simpson, K; Pachter, L; Durinck, S; Wang, N; Parvin, B; Fontenay, G; Speed, T; Garbe, J; Stampfer, M; Bayandorian, H; Dorton, S; Clark, TA; Schweitzer, A; Wyrobek, A; Feiler, H; Spellman, P; Conboy, J; Gray, JW

Author(s): Lapuk, A; Marr, H; Jakkula, L; Pedro, H; Bhattacharya, S; Purdom, E; Hu, Z; Simpson, K; Pachter, L; Durinck, S; Wang, N; Parvin, B; Fontenay, G; Speed, T; Garbe, J; Stampfer, M; Bayandorian, H; Dorton, S; Clark, TA; Schweitzer, A; Wyrobek, A; Feiler, H; Spellman, P; Conboy, J; Gray, JW;
Details: Publication Year 2010-07,Volume 8,Issue #7,Page 961-974
Journal Title: MOLECULAR CANCER RESEARCH
Publication Type: Journal Article
Abstract: 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. Mol Cancer Res; 8(7); 961-74. (C) 2010 AACR.
Publisher: AMER ASSOC CANCER RESEARCH
Keywords: GENE-EXPRESSION; CELL-LINES; IDENTIFICATION; TRANSCRIPTOME; FEATURES; NETWORK; EVENTS; ARRAYS; TUMORS; ESRP1
Publisher's Version: https://doi.org/10.1158/1541-7786.MCR-09-0528
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2010-07-01 12:00:00