Research Papers:

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

André Filipe Vieira, Ana Sofia Ribeiro, Maria Rita Dionísio, Bárbara Sousa, Ana Nobre, André Albergaria, Angélica Santiago-Gómez, Nuno Mendes, Renê Gerhard, Fernando Schmitt, Robert Brian Clarke and Joana Paredes _

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Oncotarget. 2014; 5:679-692. https://doi.org/10.18632/oncotarget.1459

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André Filipe Vieira1,2, Ana Sofia Ribeiro1, Maria Rita Dionísio1,3, Bárbara Sousa1,2, Ana Rita Nobre1,2, André Albergaria1, Angélica Santiago-Gómez4, Nuno Mendes1, Renê Gerhard1, Fernando Schmitt1,5, Robert B. Clarke4, Joana Paredes1,5

1 IPATIMUP – Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal

2 ICBAS – Institute of Biomedical Sciences Abel Salazar, Porto, Portugal

3 Gulbenkian Program for Advanced Medical Education, Lisbon, Portugal

4 Breast Biology group, Institute of Cancer Sciences, University of Manchester, Manchester UK

5 Faculty of Medicine of the University of Porto, Porto, Portugal


Joana Paredes, email:

Keywords: P-cadherin, Breast cancer, α6β4 integrin, cancer stem cells, invasion, FAK, Src

Received: October 2, 2013 Accepted: January 6, 2014 Published: January 6, 2014


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.

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