Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics.
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.
Hennessy
Bryan T
BT
Department of Gynecologic Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. bhennessy@mdanderson.org
Gonzalez-Angulo
Ana-Maria
AM
Stemke-Hale
Katherine
K
Gilcrease
Michael Z
MZ
Krishnamurthy
Savitri
S
Lee
Ju-Seog
JS
Fridlyand
Jane
J
Sahin
Aysegul
A
Agarwal
Roshan
R
Joy
Corwin
C
Liu
Wenbin
W
Stivers
David
D
Baggerly
Keith
K
Carey
Mark
M
Lluch
Ana
A
Monteagudo
Carlos
C
He
Xiaping
X
Weigman
Victor
V
Fan
Cheng
C
Palazzo
Juan
J
Hortobagyi
Gabriel N
GN
Nolden
Laura K
LK
Wang
Nicholas J
NJ
Valero
Vicente
V
Gray
Joe W
JW
Perou
Charles M
CM
Mills
Gordon B
GB
D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D004273:DNA, Neoplasm / Q000235:genetics; D004847:Epithelial Cells / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D008679:Metaplasia; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D011987:Receptors, Steroid / Q000235:genetics; D012509:Sarcoma / Q000235:genetics / Q000473:pathology; D014158:Transcription, Genetic; D018631:ras Proteins / Q000235:genetics
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D012334:RNA, Neoplasm; D011987:Receptors, Steroid; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins