Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics

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  • Hennessy, Bryan T.
    • Other Affiliation: Departments of Gynecologic Medical Oncology, Systems Biology, and Kleberg Center for Molecular Markers, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
  • Gonzalez-Angulo, Ana-Maria
    • Other Affiliation: Departments of Systems Biology, Breast Medical Oncology, and Kleberg Center for Molecular Markers, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
  • Stemke-Hale, Katherine
    • Other Affiliation: Departments of Systems Biology and Kleberg Center for Molecular Markers, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
  • Gilcrease, Michael Z.
    • Other Affiliation: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
  • Krishnamurthy, Savitri
    • Other Affiliation: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
  • Lee, Ju-Seog
    • Other Affiliation: Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
  • Fridlyand, Jane
    • Other Affiliation: Lawrence Berkeley National Laboratory, Berkeley, California
  • Sahin, Aysegul
    • Other Affiliation: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
  • Agarwal, Roshan
    • Other Affiliation: Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
  • Joy, Corwin
    • Other Affiliation: Department Bioinformatics and Computational Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
  • Liu, Wenbin
    • Other Affiliation: Department Bioinformatics and Computational Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
  • Stivers, David
    • Other Affiliation: Department Bioinformatics and Computational Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
  • Baggerly, Keith
    • Other Affiliation: Department Bioinformatics and Computational Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
  • Carey, Mark
    • Other Affiliation: Departments of Systems Biology and Kleberg Center for Molecular Markers, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
  • Lluch, Ana
    • Other Affiliation: Clinic Hospital, Valencia, Spain
  • Monteagudo, Carlos
    • Other Affiliation: University of Valencia, Valencia, Spain
  • He, Xiaping
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Weigman, Victor J
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Fan, Cheng
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Palazzo, Juan
    • Other Affiliation: Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania
  • Hortobagyi, Gabriel N.
    • Other Affiliation: Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
  • Nolden, Laura K.
    • Other Affiliation: Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
  • Wang, Nicholas J.
    • Other Affiliation: Lawrence Berkeley National Laboratory, Berkeley, California
  • Valero, Vicente
    • Other Affiliation: Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
  • Gray, Joe W.
    • Other Affiliation: Lawrence Berkeley National Laboratory, Berkeley, California
  • Perou, Charles
  • Mills, Gordon B.
    • Other Affiliation: Departments of Systems Biology and Kleberg Center for Molecular Markers, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
Abstract
  • Metaplastic breast cancers (MBC) are aggressive, chemoresistant tumors characterized by lineage plasticity. To advance understanding of their pathogenesis and relatedness to other breast cancer subtypes, 28 MBCs were compared with common breast cancers using comparative genomic hybridization, transcriptional profiling, and reverse-phase protein arrays and by sequencing for common breast cancer mutations. MBCs showed unique DNA copy number aberrations compared with common breast cancers. PIK3CA mutations were detected in 9 of 19 MBCs (47.4%) versus 80 of 232 hormone receptor–positive cancers (34.5%; P = 0.32), 17 of 75 HER-2–positive samples (22.7%; P = 0.04), 20 of 240 basal-like cancers (8.3%; P less than 0.0001), and 0 of 14 claudin-low tumors (P = 0.004). Of 7 phosphatidylinositol 3-kinase/AKT pathway phosphorylation sites, 6 were more highly phosphorylated in MBCs than in other breast tumor subtypes. The majority of MBCs displayed mRNA profiles different from those of the most common, including basal-like cancers. By transcriptional profiling, MBCs and the recently identified claudin-low breast cancer subset constitute related receptor-negative subgroups characterized by low expression of GATA3-regulated genes and of genes responsible for cell-cell adhesion with enrichment for markers linked to stem cell function and epithelial-to-mesenchymal transition (EMT). In contrast to other breast cancers, claudin-low tumors and most MBCs showed a significant similarity to a “tumorigenic” signature defined using CD44+/CD24− breast tumor–initiating stem cell–like cells. MBCs and claudin-low tumors are thus enriched in EMT and stem cell–like features, and may arise from an earlier, more chemoresistant breast epithelial precursor than basal-like or luminal cancers. PIK3CA mutations, EMT, and stem cell-like characteristics likely contribute to the poor outcomes of MBC and suggest novel therapeutic targets. [Cancer Res 2009;69(10):4116–24]
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  • Article
Rights statement
  • In Copyright
Journal title
  • Cancer Research
Journal volume
  • 69
Journal issue
  • 10
Page start
  • 4116
Page end
  • 4124
Language
  • English
Version
  • Postprint
ISSN
  • 1538-7445

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