posters International Association for Breast Cancer Research 2014

Rab coupling proteins is a critical regulator of ErbB2-mediated breast cancer tumorigenesis and metastasis (#17)

Pierre-Luc Boulay 1 , Julie-Émilie Huot-Marchand 1 , Cynthia Lavoie 1 , Julie M. Livingstone 2 , Laura Jones 1 , Dongmei Zuo 1 , Liliane Meunier 3 , Shirley Campbell 4 , Jim C. Norman 5 , Gordon Mills 6 , Eric Bonneil 7 , Mike Hallet 2 , Morag Park 1 , Anne-Marie Mess-Masson 3 , William J. Muller 1
  1. Department of Biochemistry, McGill University, Rosalind and Morris Goodman Cancer Research Centre, Montreal, QC, Canada
  2. Department of Bioinformatics, McGill University, Rosalind and Morris Goodman Cancer Research Centre, Montreal, QC, Canada
  3. CHUM Research Centre, Montreal, QC, Canada
  4. Department of Pharmacology, University of Montreal, Montreal, QC, Canada
  5. Cancer Research UK Beatson Institute , Glasgow, UK
  6. Department of System Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  7. Institute for Research in Immunology and Cancer, Montreal, QC, Canada

Amplification and elevated expression of Rab Coupling Protein (Rab11FIP1/RCP) has been noted in 10-25% of primary breast cancers and was further correlated with high metastatic grade and poor clinical outcome. Nevertheless, the role of RCP in Her2-positive breast cancer remains elusive. In this study, we report that RCP in the mammary epithelium acts as a critical factor in ErbB2-driven mammary tumorigenesis program as well as lung metastasis formation. We have recently generated transgenic mice that inducibly express RCP under the transcriptional control of a Tetracycline promoter. We breed these mice with transgenic mice expressing ErbB2/neuNDL. Induction of RCP expression in the ErbB2-driven model results in a tumor onset delay in addition to a drastic defect in metastasis formation. Furthermore, this gain of function of RCP promotes a significant decrease in cell proliferation with an increase in cell-capacity to enter in senescence program. Using immunohistochemical, biochemical and proteomic approaches, we demonstrated that induction of RCP promotes Senescence Associated to Heterochromatin Foci (SAHF) subtype including the H3K9 methylation signature. In addition, using in vitro 3D-cell culture we showed that RCP is essential to the maintenance of adherent junction by regulating E-cadherin endocytosis. Performing mammary fat pad injection in the athymic nude mouse model, we demonstrated that depletion of RCP in ErbB2/neuNT and ErbB2/NDL cell lines leads to a significant increase in the number of lung metastases. Importantly, gene expression profile analysis of tumor banks of human breast tumors showed that the expression of RCP is inversely correlated with HER2 levels.  

Unlike previous studies investigating the role of RCP in human breast cancer, we have uncovered a novel role of RCP whereby RCP acts as a tumor suppressor in ErbB2-driven breast cancer progression as well as metastasis program.