The mitotic kinase Aurora-A promotes distant metastases by inducing epithelial-to-mesenchymal transition in ERα+ breast cancer cells

Abstract

In this study, we demonstrate that constitutive activation of Raf-1 oncogenic signaling induces stabilization and accumulation of Aurora-A mitotic kinase that ultimately drives the transition from an epithelial to a highly invasive mesenchymal phenotype in estrogen receptor α-positive (ERα+) breast cancer cells. The transition from an epithelial- to a mesenchymal-like phenotype was characterized by reduced expression of ERα, HER-2/Neu overexpression and loss of CD24 surface receptor (CD24 –/low). Importantly, expression of key epithelial-to-mesenchymal transition (EMT) markers and upregulation of the stemness gene SOX2 was linked to acquisition of stem cell-like properties such as the ability to form mammospheres in vitro and tumor self-renewal in vivo. Moreover, aberrant Aurora-A kinase activity induced phosphorylation and nuclear translocation of SMAD5, indicating a novel interplay between Aurora-A and SMAD5 signaling pathways in the development of EMT, stemness and ultimately tumor progression. Importantly, pharmacological and molecular inhibition of Aurora-A kinase activity restored a CD24+ epithelial phenotype that was coupled to ERα expression, downregulation of HER-2/Neu, inhibition of EMT and impaired self-renewal ability, resulting in the suppression of distant metastases. Taken together, our findings show for the first time the causal role of Aurora-A kinase in the activation of EMT pathway responsible for the development of distant metastases in ERα+ breast cancer cells. Moreover, this study has important translational implications because it highlights the mitotic kinase Aurora-A as a novel promising therapeutic target to selectively eliminate highly invasive cancer cells and improve the disease-free and overall survival of ERα+ breast cancer patients resistant to conventional endocrine therapy.

USP44+ Cancer Stem Cell Subclones Contribute to Breast Cancer Aggressiveness by Promoting Vasculogenic Mimicry

“…AURKA, as the centrosome-associated kinase, not only induced centrosome abnormality, but also promoted the development of epithelial-mesenchymal transition and stemness of tumor cells (30). In accordance with previous studies, our current study found that AURKA overexpression induced extra centrosomes and stemness development in MCF-7 cells.…”

Centrosome amplification: a suspect in breast cancer and racial disparities

“…Based on these data, it seems that development of the mammalian brain and eye relies on a narrow range of PLK4 expression, with centrosome depletion and CA resulting in impaired growth due, at least in part, to mitotic defects. It is unclear whether PLK4-overexpression-driven CA results in similar phenotypes in mammary stem cells; however, tumor cells from xenografts of MCF-7 cells with constitutively active Raf-1 oncoprotein (MCF-7 ΔRaf-1 cells) exhibit mesenchymal phenotype along with upregulated AURKA expression and robust phosphorylation only in CD24 −/low (vs. CD24 + ) cells, which also exhibit CA, so AURKA may promote stem-like features through CA (D'Assoro, et al 2014). More research is needed to clarify how PLK4-overexpression-induced CA impacts mammary stem cell division and the implications for breast tumorigenesis.…”

The Aurora-A–Twist1 axis promotes highly aggressive phenotypes in pancreatic carcinoma

“…AURKA knockdown increases taxane chemosensitivity and hinders in vivo tumorigenesis (Hata et al, 2005). A recent study revealed a positive role of AURKA in promoting EMT in breast cancer and pancreatic cancer through experiments using the AURKA inhibitor Alisertib (also known as MLN8237); however, the molecular mechanism by which AURKA promotes EMT remains unclear (D'Assoro et al, 2014;Wang et al, 2015). In this study, we identified a crucial role of AURKA in promoting EMT in cells and in vivo.…”