title: TGFβ induces the formation of tumour-initiating cells in claudinlow breast cancer.
abstract: The role of transforming growth factor-beta (TGFβ) in the progression of different molecular subtypes of breast cancer has not been clarified. Here we show that TGFβ increases breast tumour-initiating cell (BTIC) numbers but only in claudin(low) breast cancer cell lines by orchestrating a specific gene signature enriched in stem cell processes that predicts worse clinical outcome in breast cancer patients. NEDD9, a member of the Cas family of integrin scaffold proteins, is necessary to mediate these TGFβ-specific effects through a positive feedback loop that integrates TGFβ/Smad and Rho-actin-SRF-dependent signals. In normal human mammary epithelium, TGFβ induces progenitor activity only in the basal/stem cell compartment, where claudin(low) cancers are presumed to arise. These data show opposing responses to TGFβ in both breast malignant cell subtypes and normal mammary epithelial cell subpopulations and suggest therapeutic strategies for a subset of human breast cancers.
authors.affiliation: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK. alex.bruna@cancer.org.uk
authors.forename: Alejandra
authors.initials: A
authors.lastname: Bruna
authors.forename: Wendy
authors.initials: W
authors.lastname: Greenwood
authors.forename: John
authors.initials: J
authors.lastname: Le Quesne
authors.forename: Andrew
authors.initials: A
authors.lastname: Teschendorff
authors.forename: Diego
authors.initials: D
authors.lastname: Miranda-Saavedra
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rueda
authors.forename: Jose L
authors.initials: JL
authors.lastname: Sandoval
authors.forename: Ana Tufegdzic
authors.initials: AT
authors.lastname: Vidakovic
authors.forename: Amel
authors.initials: A
authors.lastname: Saadi
authors.forename: Paul
authors.initials: P
authors.lastname: Pharoah
authors.forename: John
authors.initials: J
authors.lastname: Stingl
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D047369:Chromatin Immunoprecipitation; D057167:Claudins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D057167:Claudins; C099942:NEDD9 protein, human; D010750:Phosphoproteins; D016212:Transforming Growth Factor beta