TY - JOUR
T1 - Exon-level microarray analyses identify alternative splicing programs in breast cancer
AU - Lapuk, Anna
AU - Marr, Henry
AU - Jakkula, Lakshmi
AU - Pedro, Helder
AU - Bhattacharya, Sanchita
AU - Purdom, Elizabeth
AU - Hu, Zhi
AU - Simpson, Ken
AU - Pachter, Lior
AU - Durinck, Steffen
AU - Wang, Nicholas
AU - Parvin, Bahram
AU - Fontenay, Gerald
AU - Speed, Terence
AU - Garbe, James
AU - Stampfer, Martha
AU - Bayandorian, Hovig
AU - Dorton, Shannon
AU - Clark, Tyson A.
AU - Schweitzer, Anthony
AU - Wyrobek, Andrew
AU - Feiler, Heidi
AU - Spellman, Paul
AU - Conboy, John
AU - Gray, Joe W.
PY - 2010/7
Y1 - 2010/7
N2 - 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.
AB - 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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U2 - 10.1158/1541-7786.MCR-09-0528
DO - 10.1158/1541-7786.MCR-09-0528
M3 - Article
C2 - 20605923
AN - SCOPUS:77955463831
SN - 1541-7786
VL - 8
SP - 961
EP - 974
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 7
ER -