title: ALDH1-positive cancer stem cells predict engraftment of primary breast tumors and are governed by a common stem cell program.
abstract: Cancer stem-like cells (CSC) have been widely studied, but their clinical relevance has yet to be established in breast cancer. Here, we report the establishment of primary breast tumor-derived xenografts (PDX) that encompass the main diversity of human breast cancer and retain the major clinicopathologic features of primary tumors. Successful engraftment was correlated with the presence of ALDH1-positive CSCs, which predicted prognosis in patients. The xenografts we developed showed a hierarchical cell organization of breast cancer with the ALDH1-positive CSCs constituting the tumorigenic cell population. Analysis of gene expression from functionally validated CSCs yielded a breast CSC signature and identified a core transcriptional program of 19 genes shared with murine embryonic, hematopoietic, and neural stem cells. This generalized stem cell program allowed the identification of potential CSC regulators, which were related mainly to metabolic processes. Using an siRNA genetic screen designed to target the 19 genes, we validated the functional role of this stem cell program in the regulation of breast CSC biology. Our work offers a proof of the functional importance of CSCs in breast cancer, and it establishes the reliability of PDXs for use in developing personalized CSC therapies for patients with breast cancer.
authors.affiliation: Authors' Affiliations: INSERM, U1068, CRCM, Molecular Oncology, Institut Paoli-Calmettes, Biopathology, Aix-Marseille Univ, UM 105, F-13284, Départements d'Oncologie Médicale, Chirugie oncologique, and Radiologie, Institut Paoli-Calmettes, Marseille; and Plateforme ARN interference PArI, CEA SACLAY, Gif-sur-Yvette, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Charafe-Jauffret
authors.forename: Christophe
authors.initials: C
authors.lastname: Ginestier
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.forename: Olivier
authors.initials: O
authors.lastname: Cabaud
authors.forename: Julien
authors.initials: J
authors.lastname: Wicinski
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Josselin
authors.forename: José
authors.initials: J
authors.lastname: Adelaide
authors.forename: Tien-Tuan
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Florence
authors.initials: F
authors.lastname: Monville
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Jacquemier
authors.forename: Jeanne
authors.initials: J
authors.lastname: Thomassin-Piana
authors.forename: Guillaume
authors.initials: G
authors.lastname: Pinna
authors.forename: Aurélie
authors.initials: A
authors.lastname: Jalaguier
authors.forename: Eric
authors.initials: E
authors.lastname: Lambaudie
authors.forename: Gilles
authors.initials: G
authors.lastname: Houvenaeghel
authors.forename: Luc
authors.initials: L
authors.lastname: Xerri
authors.forename: Annick
authors.initials: A
authors.lastname: Harel-Bellan
authors.forename: Max
authors.initials: M
authors.lastname: Chaffanet
authors.forename: Patrice
authors.initials: P
authors.lastname: Viens
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology; D009693:Nucleic Acid Hybridization; D011379:Prognosis; D011446:Prospective Studies; D050697:Retinal Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; D007527:Isoenzymes; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase