Prognostic value of kallikrein-related peptidase 12 (KLK12) mRNA expression in triple-negative breast cancer patients

Weiwei Gong,Alexander Muckenhuber,Viktor Magdolen,Marion Kiechle,Sarah Preis,Xiaocong Geng,Julia Dorn,Yves Courty,Agnes Petit-Courty,Tobias Dreyer,Yueyang Liu,Yueyang Liu,Yueyang Liu

doi:10.1186/s10020-020-0145-7

Abstract

BackgroundThe serine protease KLK12 belongs to the human fifteen-member family of kallikrein-related peptidases. Differential expression accompanied by either increased or decreased enzymatic activity has been linked to several diseases including cancer. Triple-negative breast cancer (TNBC) represents a very aggressive subgroup of breast cancer with high tumor recurrence rates and poor patient prognosis. Here, we quantified the KLK12 mRNA expression levels in tumor tissue of TNBC patients and analyzed their prognostic value.MethodsIn the present study, KLK12 mRNA expression in tumor tissue of TNBC patients (n = 116) was determined by quantitative real-time PCR assay. The association of KLK12 mRNA levels with clinical parameters, and patients’ outcome was analyzed using Chi-square tests, Cox regression models and Kaplan-Meier survival analysis.ResultsPositive, but low KLK12 mRNA levels were detected in about half of the cases (54 out of 116; 47%), the other samples were negative for KLK12 mRNA expression. No significant association was observed between KLK12 mRNA levels and clinicopathological variables (age, lymph node status, tumor size, and histological grade). In univariate Cox analyses, positive KLK12 mRNA expression was significantly associated with shortened disease-free survival (DFS; hazard ratio [HR] = 2.12, 95% CI = 1.19–3.78, p = 0.010) as well as overall survival (OS; HR = 1.91, 95% CI = 1.04–3.50, p = 0.037). In multivariable Cox analysis, including all clinical parameters plus KLK12 mRNA, the latter - together with age - remained an independent unfavorable predictive marker for DFS (HR = 2.33, 95% CI = 1.28–4.24, p = 0.006) and showed a trend towards significance in case of OS (HR = 1.80, 95% CI = 0.96–3.38, p = 0.066).ConclusionsPositive KLK12 expression is remarkably associated with shortened DFS and OS, suggesting that KLK12 plays a tumor-supporting role in TNBC.

Highlights

The serine protease KLK12 belongs to the human fifteen-member family of kallikrein-related peptidases
The present study focuses on the analysis of KLK12 mRNA expression in tumor tissue of triple-negative breast cancer (TNBC) patients
In order to determine KLK12 mRNA expression levels in TNBC, we developed a sensitive quantitative real-time PCR assay and subsequently analyzed whether KLK12 mRNA expression is associated with established clinical variables such as age, lymph node status, tumor size, and histological grade as well as with disease-free (DFS) and overall survival time (OS) of the patients

Summary

Introduction

The serine protease KLK12 belongs to the human fifteen-member family of kallikrein-related peptidases. Tissue kallikrein (KLK1) and the kallikrein-related peptidases (KLK2–15) genes encode for a subgroup of 15 homologous secreted serine proteases with trypsin- or chymotrypsin-like activities. They are co-localized within the chromosomal region 19q13.3–4 representing the largest contiguous family of protease genes in the human genome (Diamandis et al 2000; Clements et al 2001). A number of opposing effects have been documented for KLKs in different types of malignancies indicating that their actions depend on the tumor type and/or the tumor microenvironment These divergent effects are often reflected in the unfavorable or favorable prognostic values found for the mRNA and/or protein expression levels (Avgeris et al 2012; Borgono and Diamandis 2004; Filippou et al 2016; Kryza et al 2015). Availability of such biomarkers will become a key trait for clinical practice in the future to facilitate drug development and treatment decision

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Conclusion