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Characterization of a naturally occurring breast cancer subset enriched in EMT and stem cell characteristics [electronic resource].

Published
Berkeley, Calif. : Lawrence Berkeley National Laboratory, 2009.
Oak Ridge, Tenn. : Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy.
Additional Creators
Lawrence Berkeley National Laboratory and United States. Department of Energy. Office of Scientific and Technical Information
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Summary
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.
Report Numbers
E 1.99:lbnl-1944e
lbnl-1944e
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Published through SciTech Connect.
05/19/2009.
"lbnl-1944e"
Cancer Research 69 10 0008-5472 FT
Gray, Joe W.; Fan, Cheng; Perou, Charles M.; Fridlyand, Jane; Mills, Gordon B.; Liu, Wenbin; Palazzo, Juan; Hortobagyi, Gabriel N.; Valero, Vicente; Sahin, Aysegul; Stivers, David; Carey, Mark; Wang, Nicholas J.; Lluch, Ana; Stemke-Hale, Katherine; Nolden, Laura K.; Hennessy, Bryan T.; Agarwal, Roshan; Gonzalez-Angulo, Ana-Maria; Gilcrease, Michael Z.; Krishnamurthy, Savitri; Lee, Ju-Seog; Joy, Corwin; Baggerly, Keith; Monteagudo, Carlos; He, Xiaping; Weigman, Victor.
Life Sciences Division
Funding Information
DE-AC02-05CH11231
P50 CA58207
U54 CA112970
View MARC record | catkey: 13809381