Polo-like kinase 4 (Plk4) potentiatesanoikis-resistance of p53KO mammary epithelial cells by inducing a hybrid EMT phenotype

Abstract

AbstractPolo-like kinase 4 (Plk4), the major regulator of centriole biogenesis, has emerged as a putative therapeutic target in cancer due to its abnormal expression in human carcinomas, leading to centrosome number deregulation, mitotic defects and chromosomal instability. Moreover, Plk4 deregulation promotes tumor growth and metastasis in mouse models and is significantly associated with poor patient prognosis.Here, we further investigate the role of Plk4 in carcinogenesis and show that its overexpression significantly potentiates resistance to cell death byanoikisof non-tumorigenic p53 knock-out (p53KO) mammary epithelial cells. Importantly, this effect is independent of Plk4’s role in centrosome biogenesis, suggesting that this kinase has additional cellular functions. Interestingly, the Plk4-inducedanoikisresistance is associated with the induction of a stable hybrid epithelial-mesenchymal phenotype and is partially dependent on P-cadherin upregulation. Furthermore, we found that the conditioned media of Plk4-induced p53KO mammary epithelial cells also inducesanoikisresistance of breast cancer cells in a paracrine way, being also partially dependent on soluble P-cadherin secretion.Our work shows, for the first time, that high expression levels of Plk4 induceanoikisresistance of both mammary epithelial cells with p53KO background, as well as of breast cancer cells exposed to their secretome, which is partially mediated through P-cadherin upregulation. These results reinforce the idea that Plk4, independently of its role in centrosome biogenesis, functions as an oncogene, by impacting the tumor microenvironment to promote malignancy.