title: Rab11-FIP1C Is a Critical Negative Regulator in ErbB2-Mediated Mammary Tumor Progression.
abstract: Rab coupling protein (FIP1C), an effector of the Rab11 GTPases, including Rab25, is amplified and overexpressed in 10% to 25% of primary breast cancers and correlates with poor clinical outcome. Rab25 is also frequently silenced in triple-negative breast cancer, suggesting its ability to function as either an oncogene or a tumor suppressor, depending on the breast cancer subtype. However, the pathobiologic role of FIP family members, such as FIP1C, in a tumor-specific setting remains elusive. In this study, we used ErbB2 mouse models of human breast cancer to investigate FIP1C function in tumorigenesis. Doxycycline-induced expression of FIP1C in the MMTV-ErbB2 mouse model resulted in delayed mammary tumor progression. Conversely, targeted deletion of FIP1C in the mammary epithelium of an ErbB2 model coexpressing Cre recombinase led to accelerated tumor onset. Genetic and biochemical characterization of these FIP1C-proficient and -deficient tumor models revealed that FIP1C regulated E-cadherin (CDH1) trafficking and ZONAB (YBX3) function in Cdk4-mediated cell-cycle progression. Furthermore, we demonstrate that FIP1C promoted lysosomal degradation of ErbB2. Consistent with our findings in the mouse, the expression of FIP1C was inversely correlated with ErbB2 levels in breast cancer patients. Taken together, our findings indicate that FIP1C acts as a tumor suppressor in the context of ErbB2-positive breast cancer and may be therapeutically exploited as an alternative strategy for targeting aberrant ErbB2 expression. Cancer Res; 76(9); 2662-74. ©2016 AACR.
authors.affiliation: Department of Biochemistry, McGill University, Rosalind and Morris Goodman Cancer Research Montreal, Québec, Canada.
authors.forename: Pierre-Luc
authors.initials: PL
authors.lastname: Boulay
authors.affiliation: Integrin Cell Biology Cancer Research UK Beaston Institute, Glasgow, United Kingdom.
authors.forename: Louise
authors.initials: L
authors.lastname: Mitchell
authors.affiliation: Department of Biochemistry, McGill University, Rosalind and Morris Goodman Cancer Research Montreal, Québec, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Turpin
authors.affiliation: Department of Biochemistry, McGill University, Rosalind and Morris Goodman Cancer Research Montreal, Québec, Canada.
authors.forename: Julie-Émilie
authors.initials: JÉ
authors.lastname: Huot-Marchand
authors.affiliation: Department of Biochemistry, McGill University, Rosalind and Morris Goodman Cancer Research Montreal, Québec, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lavoie
authors.affiliation: Department of Biochemistry, McGill University, Rosalind and Morris Goodman Cancer Research Montreal, Québec, Canada.
authors.forename: Virginie
authors.initials: V
authors.lastname: Sanguin-Gendreau
authors.affiliation: Department of Biochemistry, McGill University, Rosalind and Morris Goodman Cancer Research Montreal, Québec, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Jones
authors.affiliation: Department of System Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Shreya
authors.initials: S
authors.lastname: Mitra
authors.affiliation: Department of Biochemistry, McGill University, Rosalind and Morris Goodman Cancer Research Montreal, Québec, Canada.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Livingstone
authors.affiliation: Department of Pharmacology, University of Montreal, Québec, Canada.
authors.forename: Shirley
authors.initials: S
authors.lastname: Campbell
authors.affiliation: Department of Biochemistry, McGill University, Rosalind and Morris Goodman Cancer Research Montreal, Québec, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Hallett
authors.affiliation: Department of System Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Biochemistry, McGill University, Rosalind and Morris Goodman Cancer Research Montreal, Québec, Canada.
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.affiliation: Cancer Biology Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Lewis
authors.initials: L
authors.lastname: Chodosh
authors.affiliation: Integrin Cell Biology Cancer Research UK Beaston Institute, Glasgow, United Kingdom.
authors.forename: Douglas
authors.initials: D
authors.lastname: Strathdee
authors.affiliation: Integrin Cell Biology Cancer Research UK Beaston Institute, Glasgow, United Kingdom.
authors.forename: Jim C
authors.initials: JC
authors.lastname: Norman
authors.affiliation: Department of Biochemistry, McGill University, Rosalind and Morris Goodman Cancer Research Montreal, Québec, Canada. william.muller@mcgill.ca.
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000099193:rab11 GTP-Binding Proteins
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C508053:ERBB2 protein, human