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

Bryan T. Hennessy, Ana Maria Gonzalez-Angulo, Katherine Stemke-Hale, Michael Z. Gilcrease, Savitri Krishnamurthy, Ju Seog Lee, Jane Fridlyand, Aysegul Sahin, Roshan Agarwal, Corwin Joy, Wenbin Liu, David Stivers, Keith Baggerly, Mark Carey, Ana Lluch, Carlos Monteagudo, Xiaping He, Victor Weigman, Cheng Fan, Juan PalazzoGabriel N. Hortobagyi, Laura K. Nolden, Nicholas J. Wang, Vicente Valero, Joe W. Gray, Charles M. Perou, Gordon B. Mills

Research output: Contribution to journalArticle

578 Scopus citations

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, 28MBCs 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 < 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.

Original languageEnglish (US)
Pages (from-to)4116-4124
Number of pages9
JournalCancer Research
Volume69
Issue number10
DOIs
StatePublished - May 15 2009

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hennessy, B. T., Gonzalez-Angulo, A. M., Stemke-Hale, K., Gilcrease, M. Z., Krishnamurthy, S., Lee, J. S., Fridlyand, J., Sahin, A., Agarwal, R., Joy, C., Liu, W., Stivers, D., Baggerly, K., Carey, M., Lluch, A., Monteagudo, C., He, X., Weigman, V., Fan, C., ... Mills, G. B. (2009). Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Research, 69(10), 4116-4124. https://doi.org/10.1158/0008-5472.CAN-08-3441