High expression of polo-like kinase 1 is associated with TP53 inactivation, DNA repair deficiency, and worse prognosis in ER positive Her2 negative breast cancer.

Abstract

Polo-like kinase 1 (<i>PLK1</i>), the most investigated member of the <i>PLK</i> family, plays a pivotal role both in the p53-mediated regulation of DNA damage repair and in mitosis, especially in the G2/M phase. However, the evidence on the clinical and prognostic relevance of <i>PLK1</i> is limited to triple negative subtype among breast cancer (BC). We hypothesized that high expression of <i>PLK1</i> is associated with TP53 inactivation, DNA repair deficiency, and worse prognosis in ER positive in BC in a large-scale cohort should clarify its clinical relevance for each BC subtype. Total of 3173 BC cases; 1025 from TCGA cohort, 1904 from METABRIC, and 244 from neoadjuvant chemotherapy (NAC) cohort from Gene Expression Omnibus dataset, GSE32603, were analyzed. <i>PLK1</i> expressions were significantly higher in high Nottingham Grade and triple negative BC. High expression of <i>PLK1</i> was significantly associated with <i>TP53</i> mutation, high expression of <i>TP53</i> mRNA as well as protein, and it significantly correlated with the homologous recombination deficiency score. High <i>PLK1</i> expression significantly enriched cell cycle related gene sets (G2/M check point, E2F targets), MTORC1 signaling, and MYC target gene sets in the Gene Set Enrichment Analysis. High expression of <i>PLK1</i> was significantly associated with tumor infiltrating lymphocytes and tumor associated macrophages (high levels of CD8+ T cells, M0 and M1 macrophage, and low levels of M2 macrophage), and high immune cytolytic activity. While high expression of <i>PLK1</i> did not associate with pathological complete response after NAC, it was associated with poor prognosis in the whole cohort and in the ER-positive/HER2-negative subtype of TCGA. High expression of <i>PLK1</i> is significantly associated with <i>TP53</i> mutations, DNA repair deficiency and worse prognosis in BC particularly in HR+HER2- subtype. Using bioinformatics methods with large cohorts.