Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery

Jessica Kao, Keyan Salari, Melanie Bocanegra, Yoon La Choi, Luc Girard, Jeet Gandhi, Kevin A. Kwei, Tina Hernandez-Boussard, Pei Wang, Adi F. Gazdar, John D. Minna, Jonathan R. Pollack

Research output: Contribution to journalArticle

482 Scopus citations

Abstract

Background: Breast cancer cell lines have been used widely to investigate breast cancer pathobiology and new therapies. Breast cancer is a molecularly heterogeneous disease, and it is important to understand how well and which cell lines best model that diversity. In particular, microarray studies have identified molecular subtypes-luminal A, luminal B, ERBB2-associated, basal-like and normal-like-with characteristic gene-expression patterns and underlying DNA copy number alterations (CNAs). Here, we studied a collection of breast cancer cell lines to catalog molecular profiles and to assess their relation to breast cancer subtypes. Methods: Whole-genome DNA microarrays were used to profile gene expression and CNAs in a collection of 52 widely-used breast cancer cell lines, and comparisons were made to existing profiles of primary breast tumors. Hierarchical clustering was used to identify gene-expression subtypes, and Gene Set Enrichment Analysis (GSEA) to discover biological features of those subtypes. Genomic and transcriptional profiles were integrated to discover within high-amplitude CNAs candidate cancer genes with coordinately altered gene copy number and expression. Findings: Transcriptional profiling of breast cancer cell lines identified one luminal and two basal-like (A and B) subtypes. Luminal lines displayed an estrogen receptor (ER) signature and resembled luminal-A/B tumors, basal-A lines were associated with ETS-pathway and BRCA1 signatures and resembled basal-like tumors, and basal-B lines displayed mesenchymal and stem/progenitor-cell characteristics. Compared to tumors, cell lines exhibited similar patterns of CNA, but an overall higher complexity of CNA (genetically simple luminal-A tumors were not represented), and only partial conservation of subtype-specific CNAs. We identified 80 high-level DNA amplifications and 13 multi-copy deletions, and the resident genes with concomitantly altered gene-expression, highlighting known and novel candidate breast cancer genes. Conclusions: Overall, breast cancer cell lines were genetically more complex than tumors, but retained expression patterns with relevance to the luminal-basal subtype distinction. The compendium of molecular profiles defines cell lines suitable for investigations of subtype-specific pathobiology, cancer stem cell biology, biomarkers and therapies, and provides a resource for discovery of new breast cancer genes.

Original languageEnglish (US)
Article numbere6146
JournalPloS one
Volume4
Issue number7
DOIs
StatePublished - Jul 3 2009

ASJC Scopus subject areas

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

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    Kao, J., Salari, K., Bocanegra, M., Choi, Y. L., Girard, L., Gandhi, J., Kwei, K. A., Hernandez-Boussard, T., Wang, P., Gazdar, A. F., Minna, J. D., & Pollack, J. R. (2009). Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery. PloS one, 4(7), [e6146]. https://doi.org/10.1371/journal.pone.0006146