Abstract 5252: High expression of PLK1, polo-like kinase 1, is significantly associated with DNA repair deficiency, inactivated TP53, and worse prognosis in breast cancer

Abstract

Abstract Backgrounds: Polo-like kinase 1 (PLK1), the representative member of the PLK family, plays a pivotal role both in mitosis, especially in G2/M phase, and in the regulation of DNA damage repair. It is suggested that overexpression of PLK1 in cancer cells may disturb the behavior of G2-M DNA damage checkpoint for cancer cell survival. Therefore it was of interest whether PLK1 expression has any clinical significance in breast cancer (BC), which is known to have less DNA damage and mutations compared from other cancers. Methods: A total of 1025 women with BC from The Cancer Genome Atlas (TCGA) and a total of 237 women with BC from neoadjuvant (NAC) cohort are enrolled. We developed computer-based analysis to verify the clinical significance of PLK1 mRNA expression in these large BC cohorts. Results: In TCGA cohort, PLK1 high expressing tumors were statistically significantly associated with more aggressive clinical factor. Gene Set Enrichment Analysis shows that PLK1 high expressing tumors were significantly associated with cell cycle related gene sets. In addition, PLK1 high expressing tumors were significantly associated with deficiency of homologous recombination (HR), which is one of the important mechanisms of DNA repair, and high expression of TP53, which is an intermediary to the HR of PLK1. All these results suggest that PLK1 high expressing tumors associate with worse cancer biology. Recently tumor immune microenvironment (TIM) attracted many researchers’ interest for its association with better response to NAC and better survival. In analysis of TIM, we found that PLK1 high expressing tumors were significantly correlated with anti-cancer related tumor infiltrating lymphocytes (TILs) and higher immune cytolytic activity CYT. Thus, PLK1 high expressing tumors associate with TIM that is against cancer. Since both higher HR deficiency (HRD) and anti-cancer related TILs are predictors of high sensitivity to chemotherapy, response of PLK1 high expressing tumors to NAC were analyzed, which did not show significant association. On the other hand, survival analysis demonstreated that PLK1 high expressing tumors were statistically significantly associated with poor prognosis in the whole and the hormone receptor-positive/human epidermal growth factor receptor 2-negative group. Our result suggest that although PLK1 high expressing tumors attract TILs and assoaciate with HRD, those anti-tumor effects are overweighed by its association with aggressive cancer biology that translate to worse survival particularly in the subtype known to have less mutations. Conclusions: We have demonstrated the clinical significance of PLK1 mRNA expression in BC. High PLK1 expression was associated with more aggressive clinical factors, cell cycle related genes, higher HRD, inactivated TP53, high levels of TILs, and worse prognosis in BC. Citation Format: Takashi Takeshita, Mariko Asaoka, Eriko katsuta, Yan Li, Kazuaki Takabe. High expression of PLK1, polo-like kinase 1, is significantly associated with DNA repair deficiency, inactivated TP53, and worse prognosis in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5252.