Associação Portuguesa de Investigação em Cancro
A new link between P-cadherin and α6β4-integrin with implications in breast cancer progression
A new link between P-cadherin and α6β4-integrin with implications in breast cancer progression
Researchers at IPATIMUP (Joana Paredes group) are focused in P-cadherin, an adhesion molecule that induces cancer stem cell and invasive properties in breast cancer. In its newest publication, this group found a downstream signaling pathway that helps clarify P-cadherin mediated aggressive effects.
This work reports an important crosstalk between P-cadherin and the laminin receptor α6β4, a link that was never previously described. The activation of this heterodimer points to a new molecular mechanism that may be targeted to counteract the effects induced by this adhesion molecule.
Authors and Affiliations:
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
Abstract:
P-cadherin is a classical cell-cell adhesion molecule that, in contrast to E-cadherin, has a detrimental role in breast cancer progression, being an independent factor of poor prognosis 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 kinase (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 reported an important crosstalk between P-cadherin and the laminin receptor α6β4, a link that was never 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.
Journal:
Oncotarget
Link:
