Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Departments of ¹Gynecologic Medical Oncology, ²Systems Biology, ³Breast Medical Oncology, ⁴Pathology, and ⁵Bioinformatics and Computational Biology and ⁶Kleberg Center for Molecular Markers, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; ⁷Lawrence Berkeley National Laboratory, Berkeley, California; ⁸Clinic Hospital and ⁹University of Valencia, Valencia, Spain; ¹⁰Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina; and ¹¹Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania

^* To whom correspondence should be addressed. E-mail: bhennessy{at}mdanderson.org.

	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 < 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]

Key Words: Breast, Cancer, Metaplastic

This article has been cited by other articles:

				J. E. Visvader Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis Genes & Dev., November 15, 2009; 23(22): 2563 - 2577. [Abstract] [Full Text] [PDF]

				C. J. Creighton, X. Li, M. Landis, J. M. Dixon, V. M. Neumeister, A. Sjolund, D. L. Rimm, H. Wong, A. Rodriguez, J. I. Herschkowitz, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features PNAS, August 18, 2009; 106(33): 13820 - 13825. [Abstract] [Full Text] [PDF]