title: The Heterodimeric TWIST1-E12 Complex Drives the Oncogenic Potential of TWIST1 in Human Mammary Epithelial Cells.
abstract: The TWIST1 embryonic transcription factor displays biphasic functions during the course of carcinogenesis. It facilitates the escape of cells from oncogene-induced fail-safe programs (senescence, apoptosis) and their consequent neoplastic transformation. Additionally, it promotes the epithelial-to-mesenchymal transition and the initiation of the metastatic spread of cancer cells. Interestingly, cancer cells recurrently remain dependent on TWIST1 for their survival and/or proliferation, making TWIST1 their Achilles' heel. TWIST1 has been reported to form either homodimeric or heterodimeric complexes mainly in association with the E bHLH class I proteins. These complexes display distinct, sometimes even antagonistic, functions during development and unequal prometastatic functions in prostate cancer cells. Using a tethered dimer strategy, we successively assessed the ability of TWIST1 dimers to cooperate with an activated version of RAS in human mammary epithelial cell transformation, to provide mice with the ability to spontaneously develop breast tumors, and lastly to maintain a senescence program at a latent state in several breast cancer cell lines. We demonstrate that the TWIST1-E12 complex, unlike the homodimer, is an oncogenic form of TWIST1 in mammary epithelial cells and that efficient binding of both partners is a prerequisite for its activity. The detection of the heterodimer in human premalignant lesions by a proximity ligation assay, at a stage preceding the initiation of the metastatic cascade, is coherent with such an oncogenic function. TWIST1-E protein heterodimeric complexes may thus constitute the main active forms of TWIST1 with regard to senescence inhibition over the time course of breast tumorigenesis.
authors.affiliation: Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, France; LabEX DEVweCAN, Lyon, France; UNIV UMR1052, Lyon, France; Centre Léon Bérard, Lyon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Jacqueroud
authors.affiliation: Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, France; LabEX DEVweCAN, Lyon, France; UNIV UMR1052, Lyon, France; Centre Léon Bérard, Lyon, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Bouard
authors.affiliation: Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, France; LabEX DEVweCAN, Lyon, France; UNIV UMR1052, Lyon, France; Centre Léon Bérard, Lyon, France.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Richard
authors.affiliation: Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, France; LabEX DEVweCAN, Lyon, France; UNIV UMR1052, Lyon, France; Centre Léon Bérard, Lyon, France; Université de Lyon 1, ISPB, Lyon, France; Hospices Civils de Lyon, Lyon, France.
authors.forename: Léa
authors.initials: L
authors.lastname: Payen
authors.affiliation: Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, France; LabEX DEVweCAN, Lyon, France; UNIV UMR1052, Lyon, France; Centre Léon Bérard, Lyon, France; Université de Lyon 1, ISPB, Lyon, France; Hospices Civils de Lyon, Lyon, France; Hôpital de la Croix-Rousse, Lyon, France.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Devouassoux-Shisheboran
authors.affiliation: Center for Molecular Medicine, Main Medical Center Research Institute, Scarborough, ME, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Spicer
authors.affiliation: Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, France; LabEX DEVweCAN, Lyon, France; UNIV UMR1052, Lyon, France; Centre Léon Bérard, Lyon, France; Université de Lyon 1, ISPB, Lyon, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Caramel
authors.affiliation: Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, France; LabEX DEVweCAN, Lyon, France; UNIV UMR1052, Lyon, France; Centre Léon Bérard, Lyon, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Collin
authors.affiliation: Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, France; LabEX DEVweCAN, Lyon, France; UNIV UMR1052, Lyon, France; Centre Léon Bérard, Lyon, France; Université de Lyon 1, ISPB, Lyon, France; Institut Universitaire de France, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Puisieux
authors.affiliation: Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, France; LabEX DEVweCAN, Lyon, France; UNIV UMR1052, Lyon, France; Centre Léon Bérard, Lyon, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Tissier
authors.affiliation: Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, France; LabEX DEVweCAN, Lyon, France; UNIV UMR1052, Lyon, France; Centre Léon Bérard, Lyon, France. Electronic address: stephane.ansieau@lyon.unicancer.fr.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Ansieau
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D016922:Cellular Senescence / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D055503:Protein Multimerization; D058127:Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D058127:Transcription Factor 3; D051879:Twist-Related Protein 1