title: Claudin-2 is selectively enriched in and promotes the formation of breast cancer liver metastases through engagement of integrin complexes.
abstract: The liver represents the third most frequent site of metastasis in patients with breast cancer. We performed in vivo selection using 4T1 breast cancer cells to identify genes associated with the liver metastatic phenotype. Coincident with the loss of numerous tight-junctional proteins, we observe claudin-2 overexpression, specifically in liver-aggressive breast cancer cells. We further demonstrate that claudin-2 is both necessary and sufficient for the ability of 4T1 breast cancer cells to colonize and grow in the liver. The liver-aggressive breast cancer cells display a claudin-2-mediated increase in their ability to adhere to extracellular matrix (ECM) components, such as fibronectin and type IV collagen. Claudin-2 facilitates these cell/matrix interactions by increasing the cell surface expression of α(2)β(1)- and α(5)β(1)-integrin complexes in breast cancer cells. Indeed, claudin-2-mediated adhesion to fibronectin and type IV collagen can be blocked with neutralizing antibodies that target α(5)β(1) and α(2)β(1) complexes, respectively. Immunohistochemical analyses reveal that claudin-2, although weakly expressed in primary human breast cancers, is readily detected in all liver metastasis samples examined to date. Together, these results uncover novel roles for claudin-2 in promoting breast cancer adhesion to the ECM and define its importance during breast cancer metastasis to the liver.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Tabariès
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
authors.forename: M G
authors.initials: MG
authors.lastname: Annis
authors.forename: A
authors.initials: A
authors.lastname: Omeroglu
authors.forename: F
authors.initials: F
authors.lastname: Pepin
authors.forename: V
authors.initials: V
authors.lastname: Ouellet
authors.forename: C
authors.initials: C
authors.lastname: Russo
authors.forename: M
authors.initials: M
authors.lastname: Hassanain
authors.forename: P
authors.initials: P
authors.lastname: Metrakos
authors.forename: Z
authors.initials: Z
authors.lastname: Diaz
authors.forename: M
authors.initials: M
authors.lastname: Basik
authors.forename: N
authors.initials: N
authors.lastname: Bertos
authors.forename: M
authors.initials: M
authors.lastname: Park
authors.forename: C
authors.initials: C
authors.lastname: Guettier
authors.forename: R
authors.initials: R
authors.lastname: Adam
authors.forename: M
authors.initials: M
authors.lastname: Hallett
authors.forename: P M
authors.initials: PM
authors.lastname: Siegel
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism* / Q000473:pathology; D057167:Claudins; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D038982:Integrin alpha2beta1 / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary*; D008565:Membrane Proteins / Q000502:physiology*
chemical_list: C491875:CLDN2 protein, human; D057167:Claudins; D005353:Fibronectins; D038982:Integrin alpha2beta1; D039081:Integrin alpha5beta1; D008565:Membrane Proteins