P-cadherin signals through the laminin receptor alpha 6 beta 4 integrin to induce stem cell and invasive properties to basal-like breast cancer cells

• Type: Article in International Scientific Journal
• Date: 2014

Authors

Vieira, AF (Author) Other; Ribeiro, AS (Author) Other; Dionisio, MR (Author) Other; Sousa, B (Author) Other; Nobre, AR (Author) Other; Albergaria, A (Author) Other; Santiago Gomez, A (Author) Other; Mendes, N (Author) Other; Gerhard, R (Author) Other; Fernando Schmitt (Author) FMUP; Clarke, RB (Author) Other; Paredes, J (Author) Other

Journal

Title: Oncotarget

Vol. 5

Pages: 679-692

ISSN: 1949-2553

Publisher: Impact Journals

Indexing

ISI Web of Knowledge - 46 Citations

Scopus - 46 Citations

Other information

Authenticus ID: P-009-KQ1

Abstract (EN): 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 alpha 6 beta 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 alpha 6 integrin subunit expression and directly interacts with the beta 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, alpha 6 beta 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 alpha 6 beta 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14