Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer.
OBJECTIVE
To examine the role of cancer stem cells (CSC) in mediating metastasis in inflammatory breast cancer (IBC) and the association of these cells with patient outcome in this aggressive type of breast cancer.


METHODS
CSCs were isolated from SUM149 and MARY-X, an IBC cell line and primary xenograft, by virtue of increased aldehyde dehydrogenase (ALDH) activity as assessed by the ALDEFLUOR assay. Invasion and metastasis of CSC populations were assessed by in vitro and mouse xenograft assays. Expression of ALDH1 was determined on a retrospective series of 109 IBC patients and this was correlated with histoclinical data. All statistical tests were two sided. Log-rank tests using Kaplan-Meier analysis were used to determine the correlation of ALDH1 expression with development of metastasis and patient outcome.


RESULTS
Both in vitro and xenograft assays showed that invasion and metastasis in IBC are mediated by a cellular component that displays ALDH activity. Furthermore, expression of ALDH1 in IBC was an independent predictive factor for early metastasis and decreased survival in this patient population.


CONCLUSIONS
These results suggest that the metastatic, aggressive behavior of IBC may be mediated by a CSC component that displays ALDH enzymatic activity. ALDH1 expression represents the first independent prognostic marker to predict metastasis and poor patient outcome in IBC. The results illustrate how stem cell research can translate into clinical practice in the IBC field.
Charafe-Jauffret
Emmanuelle
E
Department of Molecular Oncology, Institut Paoli-Calmettes/UMR891 Institut National de la Sante et de la Recherche Medicale, Université de la Méditerranée, Marseille Cancer Research Center, Marseille, France. jauffrete@marseille.fnclcc.fr
Ginestier
Christophe
C
Iovino
Flora
F
Tarpin
Carole
C
Diebel
Mark
M
Esterni
Benjamin
B
Houvenaeghel
Gilles
G
Extra
Jean-Marc
JM
Bertucci
François
F
Jacquemier
Jocelyne
J
Xerri
Luc
L
Dontu
Gabriela
G
Stassi
Giorgio
G
Xiao
Yi
Y
Barsky
Sanford H
SH
Birnbaum
Daniel
D
Viens
Patrice
P
Wicha
Max S
MS
D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007249:Inflammation / Q000201:enzymology*; D007527:Isoenzymes / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000201:enzymology*; D050697:Retinal Dehydrogenase; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D007527:Isoenzymes; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase