title: P-cadherin signals through the laminin receptor α6β4 integrin to induce stem cell and invasive properties in basal-like breast cancer cells.
abstract: P-cadherin is a classical cell-cell adhesion molecule that, in contrast to E-cadherin, has a positive role in breast cancer progression, being considered a poor prognostic factor in this disease. In previous reports, we have shown that this protein induces cancer stem cell and invasive properties to basal-like breast cancer cells. Here, we clarify the downstream signaling pathways that are triggered by P-cadherin to mediate these effects. We demonstrated that P-cadherin inhibition led to a significant decreased adhesion of cancer cells to the basement membrane substrate laminin, as well as to a major reduction in the expression of the laminin receptor α6β4 integrin. Remarkably, the expression of this heterodimer was required for the invasive capacity and increased mammosphere forming efficiency induced by P-cadherin expression. Moreover, we showed that P-cadherin transcriptionally up-regulates the α6 integrin subunit expression and directly interacts with the β4 integrin subunit. We still showed that P-cadherin downstream signaling, in response to laminin, involves the activation of focal adhesion (FAK), Src and AKT kinases. The association between the expression of P-cadherin, α6β4 heterodimer and the active FAK and Src phosphorylated forms was validated in vivo. Our data establish that there is a crosstalk between P-cadherin and the laminin receptor α6β4 integrin signaling pathway, which link has never been previously described. The activation of this heterodimer explains the stem cell and invasive properties induced by P-cadherin to breast cancer cells, pointing to a new molecular mechanism that may be targeted to counteract the effects induced by this adhesion molecule.
authors.affiliation: IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.
authors.forename: André Filipe
authors.initials: AF
authors.lastname: Vieira
authors.forename: Ana Sofia
authors.initials: AS
authors.lastname: Ribeiro
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Dionísio
authors.forename: Bárbara
authors.initials: B
authors.lastname: Sousa
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Nobre
authors.forename: André
authors.initials: A
authors.lastname: Albergaria
authors.forename: Angélica
authors.initials: A
authors.lastname: Santiago-Gómez
authors.forename: Nuno
authors.initials: N
authors.lastname: Mendes
authors.forename: Renê
authors.initials: R
authors.lastname: Gerhard
authors.forename: Fernando
authors.initials: F
authors.lastname: Schmitt
authors.forename: Robert B
authors.initials: RB
authors.lastname: Clarke
authors.forename: Joana
authors.initials: J
authors.lastname: Paredes
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D064593:Heterografts; D006801:Humans; D039161:Integrin alpha6beta4 / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D015820:Cadherins; D039161:Integrin alpha6beta4