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P-cadherin signals through the laminin receptor ?6?4 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 ?6?4 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 ?6 integrin subunit expression and directly interacts with the ?4 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, ?6?4 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 ?6?4 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.

SUBMITTER: Vieira AF 

PROVIDER: S-EPMC3996674 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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P-cadherin signals through the laminin receptor α6β4 integrin to induce stem cell and invasive properties in basal-like breast cancer cells.

Vieira André Filipe AF   Ribeiro Ana Sofia AS   Dionísio Maria Rita MR   Sousa Bárbara B   Nobre Ana Rita AR   Albergaria André A   Santiago-Gómez Angélica A   Mendes Nuno N   Gerhard Renê R   Schmitt Fernando F   Clarke Robert B RB   Paredes Joana J  

Oncotarget 20140201 3


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 signi  ...[more]

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