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The butterfly effect in cancer: A single base mutation can remodel the cell

Academic Article
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Overview

authors

  • Hart, J. R.
  • Zhang, Y.
  • Liao, L.
  • Ueno, L.
  • Du, L.
  • Jonkers, M.
  • Yates III, John
  • Vogt, Peter K.

publication date

  • January 2015

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • We have compared the proteome, transcriptome, and metabolome of two cell lines: the human breast epithelial line MCF-10A and its mutant descendant MCF-10A-H1047R. These cell lines are derived from the same parental stock and differ by a single amino acid substitution (H1047R) caused by a single nucleotide change in one allele of the PIK3CA gene, which encodes the catalytic subunit p110? of PI3K (phosphatidylinositol 3-kinase). They are considered isogenic. The H1047R mutation of PIK3CA is one of the most frequently encountered somatic cancer-specific mutations. In MCF-10A, this mutation induces an extensive cellular reorganization that far exceeds the known signaling activities of PI3K. The changes are highly diverse, with examples in structural protein levels, the DNA repair machinery, and sterol synthesis. Gene set enrichment analysis reveals a highly significant concordance of the genes differentially expressed in MCF-10A-H1047R cells and the established protein and RNA signatures of basal breast cancer. No such concordance was found with the specific gene signatures of other histological types of breast cancer. Our data document the power of a single base mutation, inducing an extensive remodeling of the cell toward the phenotype of a specific cancer.
  • We have compared the proteome, transcriptome, and metabolome of two cell lines: the human breast epithelial line MCF-10A and its mutant descendant MCF-10A-H1047R. These cell lines are derived from the same parental stock and differ by a single amino acid substitution (H1047R) caused by a single nucleotide change in one allele of the PIK3CA gene, which encodes the catalytic subunit p110α of PI3K (phosphatidylinositol 3-kinase). They are considered isogenic. The H1047R mutation of PIK3CA is one of the most frequently encountered somatic cancer-specific mutations. In MCF-10A, this mutation induces an extensive cellular reorganization that far exceeds the known signaling activities of PI3K. The changes are highly diverse, with examples in structural protein levels, the DNA repair machinery, and sterol synthesis. Gene set enrichment analysis reveals a highly significant concordance of the genes differentially expressed in MCF-10A-H1047R cells and the established protein and RNA signatures of basal breast cancer. No such concordance was found with the specific gene signatures of other histological types of breast cancer. Our data document the power of a single base mutation, inducing an extensive remodeling of the cell toward the phenotype of a specific cancer.

subject areas

  • Amino Acid Substitution
  • Breast Neoplasms
  • Cell Line, Tumor
  • DNA Mutational Analysis
  • DNA Repair
  • Female
  • Humans
  • Mutation, Missense
  • Neoplasm Proteins
  • Phosphatidylinositol 3-Kinases
  • RNA, Neoplasm
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Research

keywords

  • RNAseq
  • SILAC
  • basal breast cancer
  • knock-in
  • molecular signature
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Identity

PubMed Central ID

  • PMC4313835

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1424012112

PubMed ID

  • 25583473
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Additional Document Info

start page

  • 1131

end page

  • 1136

volume

  • 112

issue

  • 4

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