Abstract
The controlled formation and stabilization of E-cadherin-based adhesions is vital for epithelial integrity. This requires co-operation between the E-cadherin-based adhesions and the associated actin cytoskeleton. In cancer, this co-operation often fails, predisposing cells to migration through molecular mechanisms that have only been partially characterized. Here, we demonstrate that the actin filament cross-linker α-actinin-1 is frequently increased in human breast cancer. In mammary epithelial cells, the increased α-actinin-1 levels promote cell migration and induce disorganized acini-like structures in Matrigel. This is accompanied by a major reorganization of the actin cytoskeleton and the associated E-cadherin-based adhesions. Increased expression of α-actinin-1 is particularly noted in basal-like breast cancer cell lines, and in breast cancer patients it associates with poor prognosis in basal-like subtypes. Downregulation of α-actinin-1 in E-cadherin expressing basal-like breast cancer cells demonstrate that α-actinin-1-assembled actin fibers destabilize E-cadherin-based adhesions. Taken together, these results indicate that increased α-actinin-1 expression destabilizes E-cadherin-based adhesions, which is likely to promote the migratory potential of breast cancer cells. Furthermore, our results identify α-actinin-1 as a candidate prognostic biomarker in basal-like breast cancer.
Highlights
The dynamic actin cytoskeleton co-operates with E-cadherin- and integrin-based cell-cell or cell-matrix adhesions to maintain polarized epithelial organization and to generate the force required for cell shape changes and cell migration in remodeling tissues [1]
In breast cancer cells, increased α-actinin-1 reorganizes the actin cytoskeleton, resulting in the destabilization of Ecadherin-based adhesions without affecting E-cadherin expression levels. These results demonstrate that increased α-actinin-1 expression can contribute to cancer progression through partial epithelial to mesenchymal transition (EMT)
Partial EMT is highly relevant, as growing evidence has suggested that a significant portion of cancer cells collectively escape from primary tumors instead of the traditional EMT model, where single cells escape [2, 7, 8, 41]
Summary
The dynamic actin cytoskeleton co-operates with E-cadherin- and integrin-based cell-cell or cell-matrix adhesions to maintain polarized epithelial organization and to generate the force required for cell shape changes and cell migration in remodeling tissues [1]. Taken together, these results demonstrate that increased α-actinin-1 expression in mammary epithelial cells results in the major reorganization of the actin cytoskeleton and associated Ecadherin-based adhesions without altering E-cadherin levels. These results demonstrate that increased α-actinin-1 expression in mammary epithelial cells results in the major reorganization of the actin cytoskeleton and associated Ecadherin-based adhesions without altering E-cadherin levels This is accompanied by increased cell migration and a loss of polarized acini-like structures. To further study the relationship between increased α-actinin-1 and E-cadherin in basal-like breast cancer cells, we re-expressed GFP (control) or GFP-tagged E-cadherin (+ E-cadherin) in mesenchymal-like MDA-MB-231 cells, which lack ER and E-cadherin expression and have high α-actinin-1 levels (ER-/high A1/Ecad-) We subjected these cells to siRNA-mediated downregulation of control (siNT) or α-actinin-1 (siA1) genes (Fig 4A).
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