An integrated model of the transcriptome of HER2-positive breast cancer

Krishna R Kalari, Brian M. Necela, Xiaojia Tang, Kevin J. Thompson, Melissa Lau, Jeanette E Eckel-Passow, Jennifer M. Kachergus, S. Keith Anderson, Zhifu D Sun, Saurabh Baheti, Jennifer M. Carr, Tiffany R. Baker, Poulami Barman, Derek C Radisky, Richard W Joseph, Sarah A. McLaughlin, High Seng Chai, Stephan Camille, David Rossell, Yan AsmannE Aubrey Thompson, Edith A. Perez

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Our goal in these analyses was to use genomic features from a test set of primary breast tumors to build an integrated transcriptome landscape model that makes relevant hypothetical predictions about the biological and/or clinical behavior of HER2-positive breast cancer. We interrogated RNA-Seq data from benign breast lesions, ER+, triple negative, and HER2-positive tumors to identify 685 differentially expressed genes, 102 alternatively spliced genes, and 303 genes that expressed single nucleotide sequence variants (eSNVs) that were associated with the HER2-positive tumors in our survey panel. These features were integrated into a transcriptome landscape model that identified 12 highly interconnected genomic modules, each of which represents a cellular processes pathway that appears to define the genomic architecture of the HER2-positive tumors in our test set. The generality of the model was confirmed by the observation that several key pathways were enriched in HER2-positive TCGA breast tumors. The ability of this model to make relevant predictions about the biology of breast cancer cells was established by the observation that integrin signaling was linked to lapatinib sensitivity in vitro and strongly associated with risk of relapse in the NCCTG N9831 adjuvant trastuzumab clinical trial dataset. Additional modules from the HER2 transcriptome model, including ubiquitin-mediated proteolysis, TGF-beta signaling, RHO-family GTPase signaling, and M-phase progression, were linked to response to lapatinib and paclitaxel in vitro and/or risk of relapse in the N9831 dataset. These data indicate that an integrated transcriptome landscape model derived from a test set of HER2-positive breast tumors has potential for predicting outcome and for identifying novel potential therapeutic strategies for this breast cancer subtype.

Original languageEnglish (US)
Article numbere79298
JournalPLoS One
Volume8
Issue number11
DOIs
StatePublished - Nov 2013

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Transcriptome
transcriptome
breast neoplasms
Tumors
Breast Neoplasms
relapse
genomics
neoplasms
Genes
Proteolysis
Recurrence
Neoplasms
paclitaxel
prediction
genes
Recombinant DNA
GTP Phosphohydrolases
alternative splicing
testing
integrins

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

An integrated model of the transcriptome of HER2-positive breast cancer. / Kalari, Krishna R; Necela, Brian M.; Tang, Xiaojia; Thompson, Kevin J.; Lau, Melissa; Eckel-Passow, Jeanette E; Kachergus, Jennifer M.; Keith Anderson, S.; Sun, Zhifu D; Baheti, Saurabh; Carr, Jennifer M.; Baker, Tiffany R.; Barman, Poulami; Radisky, Derek C; Joseph, Richard W; McLaughlin, Sarah A.; Chai, High Seng; Camille, Stephan; Rossell, David; Asmann, Yan; Thompson, E Aubrey; Perez, Edith A.

In: PLoS One, Vol. 8, No. 11, e79298, 11.2013.

Research output: Contribution to journalArticle

Kalari, KR, Necela, BM, Tang, X, Thompson, KJ, Lau, M, Eckel-Passow, JE, Kachergus, JM, Keith Anderson, S, Sun, ZD, Baheti, S, Carr, JM, Baker, TR, Barman, P, Radisky, DC, Joseph, RW, McLaughlin, SA, Chai, HS, Camille, S, Rossell, D, Asmann, Y, Thompson, EA & Perez, EA 2013, 'An integrated model of the transcriptome of HER2-positive breast cancer', PLoS One, vol. 8, no. 11, e79298. https://doi.org/10.1371/journal.pone.0079298
Kalari, Krishna R ; Necela, Brian M. ; Tang, Xiaojia ; Thompson, Kevin J. ; Lau, Melissa ; Eckel-Passow, Jeanette E ; Kachergus, Jennifer M. ; Keith Anderson, S. ; Sun, Zhifu D ; Baheti, Saurabh ; Carr, Jennifer M. ; Baker, Tiffany R. ; Barman, Poulami ; Radisky, Derek C ; Joseph, Richard W ; McLaughlin, Sarah A. ; Chai, High Seng ; Camille, Stephan ; Rossell, David ; Asmann, Yan ; Thompson, E Aubrey ; Perez, Edith A. / An integrated model of the transcriptome of HER2-positive breast cancer. In: PLoS One. 2013 ; Vol. 8, No. 11.
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AU - Lau, Melissa

AU - Eckel-Passow, Jeanette E

AU - Kachergus, Jennifer M.

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AU - Barman, Poulami

AU - Radisky, Derek C

AU - Joseph, Richard W

AU - McLaughlin, Sarah A.

AU - Chai, High Seng

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AU - Rossell, David

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AU - Thompson, E Aubrey

AU - Perez, Edith A.

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