P-cadherin signals through the laminin receptor α6β4 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 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.

The potential of Beclin 1 as a therapeutic target for the treatment of breast cancer

“…High Beclin 1 expression has also been noted in mammospheres, which are breast cancer stem celllike/progenitor cells in human breast cancer and in breast cancer cell lines [72]. The fact that breast cancer stem celllike/progenitor cells are associated with basal-like breast cancer supports the high Beclin 1 expression in TNBC [90,91]. In a study of IDC TNBC, Beclin 1 expression was higher in the molecular apocrine subtype compared with other TNBC subtypes [86].…”

“…Head and neck cancer Approved [90] Beclin 1 inhibitor spautin-1 PIP3KCIII/Vps34 Promoted degradation of PI3KCIII/Vps34 complex Breast cancer cell line Preclinical [92] Xestospongin [93] 3-Methyladenine PIP3KCIII/Vps34 Inhibition of autophagy by targeting PI3KCIII…”

Membrane translocation of t-SNARE protein syntaxin-4 abrogates ground-state pluripotency in mouse embryonic stem cells

“…This study detected P-cadherin localization to the cell membrane rather than to cell–cell contact sites, suggesting that the P-cadherin-dependent morphological changes involved a function other than that in intercellular adhesion. Alternatively, certain cell surface molecules that can associate with P-cadherin but not E-cadherin—for example, integrin α6β418—could propagate signals for morphological changes.…”

“…In addition, considerable attention has been given to P-cadherin, an alternative cadherin that is upregulated during EMT. Increased expression of P-cadherin has been detected in many cancer cells18, and P-cadherin appears to promote aggressive/invasive properties in several tumor cells19. Zscan4 family members have recently emerged as key factors that maintain ground-state pluripotency.…”

Elevated integrin α6β4 expression is associated with venous invasion and decreased overall survival in non–small cell lung cancer

“…CD44 is a transmembrane glycoprotein that has been shown to facilitate many aspects of tumor progression and is important in promoting resistance to therapy [27, 28]. Interestingly, integrin β4 has been implicated in promoting stem cell like properties in breast cancer [29], and has been identified in the cancer stem cell population in NSCLC [30]. In addition, we found that expression of the integrin β4 gene is correlated with that of its binding partner, integrin α6 (CD49f), a known stem cell marker [31].…”