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Robust stratification of breast cancer subtypes using differential patterns of transcript isoform expression

Breast cancer, the second leading cause of cancer death of women worldwide, is a heterogenous disease with multiple different subtypes. These subtypes carry important implications for prognosis and therapy. Interestingly, it is known that these different subtypes not only have different biological b...

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Autores principales: Stricker, Thomas P., Brown, Christopher D., Bandlamudi, Chaitanya, McNerney, Megan, Kittler, Ralf, Montoya, Vanessa, Peterson, April, Grossman, Robert, White, Kevin P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367891/
https://www.ncbi.nlm.nih.gov/pubmed/28263985
http://dx.doi.org/10.1371/journal.pgen.1006589
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author Stricker, Thomas P.
Brown, Christopher D.
Bandlamudi, Chaitanya
McNerney, Megan
Kittler, Ralf
Montoya, Vanessa
Peterson, April
Grossman, Robert
White, Kevin P.
author_facet Stricker, Thomas P.
Brown, Christopher D.
Bandlamudi, Chaitanya
McNerney, Megan
Kittler, Ralf
Montoya, Vanessa
Peterson, April
Grossman, Robert
White, Kevin P.
author_sort Stricker, Thomas P.
collection PubMed
description Breast cancer, the second leading cause of cancer death of women worldwide, is a heterogenous disease with multiple different subtypes. These subtypes carry important implications for prognosis and therapy. Interestingly, it is known that these different subtypes not only have different biological behaviors, but also have distinct gene expression profiles. However, it has not been rigorously explored whether particular transcriptional isoforms are also differentially expressed among breast cancer subtypes, or whether transcript isoforms from the same sets of genes can be used to differentiate subtypes. To address these questions, we analyzed the patterns of transcript isoform expression using a small set of RNA-sequencing data for eleven Estrogen Receptor positive (ER+) subtype and fourteen triple negative (TN) subtype tumors. We identified specific sets of isoforms that distinguish these tumor subtypes with higher fidelity than standard mRNA expression profiles. We found that alternate promoter usage, alternative splicing, and alternate 3’UTR usage are differentially regulated in breast cancer subtypes. Profiling of isoform expression in a second, independent cohort of 68 tumors confirmed that expression of splice isoforms differentiates breast cancer subtypes. Furthermore, analysis of RNAseq data from 594 cases from the TCGA cohort confirmed the ability of isoform usage to distinguish breast cancer subtypes. Also using our expression data, we identified several RNA processing factors that were differentially expressed between tumor subtypes and/or regulated by estrogen receptor, including YBX1, YBX2, MAGOH, MAGOHB, and PCBP2. RNAi knock-down of these RNA processing factors in MCF7 cells altered isoform expression. These results indicate that global dysregulation of splicing in breast cancer occurs in a subtype-specific and reproducible manner and is driven by specific differentially expressed RNA processing factors.
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spelling pubmed-53678912017-04-06 Robust stratification of breast cancer subtypes using differential patterns of transcript isoform expression Stricker, Thomas P. Brown, Christopher D. Bandlamudi, Chaitanya McNerney, Megan Kittler, Ralf Montoya, Vanessa Peterson, April Grossman, Robert White, Kevin P. PLoS Genet Research Article Breast cancer, the second leading cause of cancer death of women worldwide, is a heterogenous disease with multiple different subtypes. These subtypes carry important implications for prognosis and therapy. Interestingly, it is known that these different subtypes not only have different biological behaviors, but also have distinct gene expression profiles. However, it has not been rigorously explored whether particular transcriptional isoforms are also differentially expressed among breast cancer subtypes, or whether transcript isoforms from the same sets of genes can be used to differentiate subtypes. To address these questions, we analyzed the patterns of transcript isoform expression using a small set of RNA-sequencing data for eleven Estrogen Receptor positive (ER+) subtype and fourteen triple negative (TN) subtype tumors. We identified specific sets of isoforms that distinguish these tumor subtypes with higher fidelity than standard mRNA expression profiles. We found that alternate promoter usage, alternative splicing, and alternate 3’UTR usage are differentially regulated in breast cancer subtypes. Profiling of isoform expression in a second, independent cohort of 68 tumors confirmed that expression of splice isoforms differentiates breast cancer subtypes. Furthermore, analysis of RNAseq data from 594 cases from the TCGA cohort confirmed the ability of isoform usage to distinguish breast cancer subtypes. Also using our expression data, we identified several RNA processing factors that were differentially expressed between tumor subtypes and/or regulated by estrogen receptor, including YBX1, YBX2, MAGOH, MAGOHB, and PCBP2. RNAi knock-down of these RNA processing factors in MCF7 cells altered isoform expression. These results indicate that global dysregulation of splicing in breast cancer occurs in a subtype-specific and reproducible manner and is driven by specific differentially expressed RNA processing factors. Public Library of Science 2017-03-06 /pmc/articles/PMC5367891/ /pubmed/28263985 http://dx.doi.org/10.1371/journal.pgen.1006589 Text en © 2017 Stricker et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Stricker, Thomas P.
Brown, Christopher D.
Bandlamudi, Chaitanya
McNerney, Megan
Kittler, Ralf
Montoya, Vanessa
Peterson, April
Grossman, Robert
White, Kevin P.
Robust stratification of breast cancer subtypes using differential patterns of transcript isoform expression
title Robust stratification of breast cancer subtypes using differential patterns of transcript isoform expression
title_full Robust stratification of breast cancer subtypes using differential patterns of transcript isoform expression
title_fullStr Robust stratification of breast cancer subtypes using differential patterns of transcript isoform expression
title_full_unstemmed Robust stratification of breast cancer subtypes using differential patterns of transcript isoform expression
title_short Robust stratification of breast cancer subtypes using differential patterns of transcript isoform expression
title_sort robust stratification of breast cancer subtypes using differential patterns of transcript isoform expression
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367891/
https://www.ncbi.nlm.nih.gov/pubmed/28263985
http://dx.doi.org/10.1371/journal.pgen.1006589
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