Cytosolic Hsp90α and its mitochondrial isoform Trap1 are differentially required in a breast cancer model

// Evangelia Vartholomaiou 1,* , Marta Madon-Simon 1,* , Stephane Hagmann 1 , Guillaume Muhlebach 1 , Wolfgang Wurst 2,3,4,5 , Thomas Floss 2 and Didier Picard 1 1 Departement de Biologie Cellulaire, Universite de Geneve, Sciences III, Geneve, Switzerland 2 Helmholtz Zentrum Munchen, Deutsches Forschungszentrum fur Gesundheit und Umwelt, Neuherberg, Germany 3 Deutsches Zentrum fur Neurodegenerative Erkrankungen e. V., Munchen, Germany 4 Munich Cluster for Systems Neurology, Munchen, Germany 5 Technische Universitat Munchen-Weihenstephan, Neuherberg, Germany * These authors have contributed equally to this work Correspondence: Didier Picard, email: // Keywords : Hsp90; Trap1; breast cancer; metastasis; mouse model Received : January 12, 2017 Accepted : February 15, 2017 Published : February 23, 2017 Abstract The Hsp90 family of molecular chaperones includes the cytosolic isoforms Hsp90α and Hsp90β, and the mitochondrial isoform Trap1. Hsp90α/β support a large number of client proteins in the cytoplasm and the nucleus whereas Trap1 regulates oxidative phosphorylation in mitochondria. Many of the associated proteins and cellular processes are relevant to cancer, and there is ample pharmacological and genetic evidence to support the idea that Hsp90α/β and Trap1 are required for tumorigenesis. However, a direct and comparative genetic test in a mouse cancer model has not been done. Here we report the effects of deleting the Hsp90α or Trap1 genes in a mouse model of breast cancer. Neither Hsp90α nor Trap1 are absolutely required for mammary tumor initiation, growth and metastasis induced by the polyoma middle T-antigen as oncogene. However, they do modulate growth and lung metastasis in vivo and cell proliferation, migration and invasion of isolated primary carcinoma cells in vitro . Without Hsp90α, tumor burden and metastasis are reduced, correlating with impaired proliferation, migration and invasion of cells in culture. Without Trap1, the appearance of tumors is initially delayed, and isolated cells are affected similarly to those without Hsp90α. Analysis of expression data of human breast cancers supports the conclusion that this is a valid mouse model highlighting the importance of these molecular chaperones.