Journal
ONCOTARGET
Volume 5, Issue 3, Pages 679-692Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.1459
Keywords
P-cadherin; Breast cancer; alpha 6 beta 4 integrin; cancer stem cells; invasion; FAK; Src
Categories
Funding
- Fundacao para a Ciencia e Tecnologia (FCT), Portugal
- Fundacao Gulbenkian
- Fundacao Champalimaud
- Portuguese Ministry of Science, Technology and Higher Education
- FCT, Portugal
- FCT
- Breast Cancer Campaign Senior Research Fellowship
- [SFRH/BPD/90303/2012]
- [SFRH/BPD/75705/2011]
- [SFRH/BD/69353/2010]
- [PTDC/SAU-GMG/120049/2010]
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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.
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