title: A new role of the Rac-GAP β2-chimaerin in cell adhesion reveals opposite functions in breast cancer initiation and tumor progression.
abstract: β2-chimaerin is a Rac1-specific negative regulator and a candidate tumor suppressor in breast cancer but its precise function in mammary tumorigenesis in vivo is unknown. Here, we study for the first time the role of β2-chimaerin in breast cancer using a mouse model and describe an unforeseen role for this protein in epithelial cell-cell adhesion. We demonstrate that expression of β2-chimaerin in breast cancer epithelial cells reduces E-cadherin protein levels, thus loosening cell-cell contacts. In vivo, genetic ablation of β2-chimaerin in the MMTV-Neu/ErbB2 mice accelerates tumor onset, but delays tumor progression. Finally, analysis of clinical databases revealed an inverse correlation between β2-chimaerin and E-cadherin gene expressions in Her2+ breast tumors. Furthermore, breast cancer patients with low β2-chimaerin expression have reduced relapse free survival but develop metastasis at similar times. Overall, our data redefine the role of β2-chimaerin as tumor suppressor and provide the first in vivo evidence of a dual function in breast cancer, suppressing tumor initiation but favoring tumor progression.
authors.affiliation: Instituto de Biología y Genética Molecular (IBGM), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Valladolid, 47003 Valladolid, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Casado-Medrano
authors.affiliation: Current address: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Barrio-Real
authors.affiliation: Instituto de Biología y Genética Molecular (IBGM), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Valladolid, 47003 Valladolid, Spain.
authors.forename: Ginesa
authors.initials: G
authors.lastname: García-Rostán
authors.affiliation: Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Matti
authors.initials: M
authors.lastname: Baumann
authors.affiliation: Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Rocks
authors.affiliation: Instituto de Biología y Genética Molecular (IBGM), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Valladolid, 47003 Valladolid, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Caloca
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; C079844:beta-chimaerin
keywords: E-cadherin; Rac1; breast cancer; metastasis; β2-chimaerin