Kallikrein-related peptidase 5 induces miRNA-mediated anti-oncogenic pathways in breast cancer

Konstantinos G Sidiropoulos,Qiang Ding,George M Yousef,Heba Khella,Joseph N Samuel,Georgios Pampalakis,Nicole M.A White,Georgia Sotiropoulou,Peter Boulos,Anna Bui

doi:10.18632/oncoscience.91

Abstract

Kallikrein-related peptidase 5 (KLK5) displays aberrant expression in cancer. Recently, we showed KLK5 reconstitution in breast cancer cell lines suppresses malignancy. Present study aims to investigate the functional KLK5 mediated miRNA network on breast cancer progression, molecular subtype and survival. 28 miRNAs were up-regulated and 62 miRNAs were down-regulated upon KLK5 expression. Extracellular matrix (ECM) molecules and cell-adhesion pathways were the most significant KLK5-induced miRNA-mediated regulatory targets. Validation from The Cancer Genome Atlas (TCGA) database indicated KLK5 was specifically down-regulated in luminal B and basal-like breast cancer subtypes. There was a correlation between KLK5, miRNAs and their downstream ECM gene targets. Long-term patient survival correlated with dysregulation of KLK5 and interacting ECM target genes. It suggests biological differences between breast cancer molecular subtypes, patient survival, and their propensity for invasion and metastasis can be explained in part by altered miRNA networks induced by KLK5 dysregulation. We provide the first evidence that KLK5 can affect miRNA networks, which regulate MMPs and other novel ECM targets and a new compelling hypothesis of interplay between serine proteases and miRNAs. We developed a combined KLK5-(ITGB1+COL12A1) predictive score for recurrence-free survival that could be exploited in clinical applications.

Highlights

Breast cancer is the most common cancer and the leading cause of death of cancer for women [1]
The top 10 up- and downregulated miRNAs are shown in Table 1.Overall, there was a significant trend of miRNA down-regulation with KLK5 expression with a mean of -30.67 fold reduction (SD = 36.13, SEM = 2.950). 10% Percentile = -86.72 fold reduction; 90% Percentile= +3.602 fold increase (Figure 1)
In line with recent literature documenting the critical involvement of miRNAs in oncogenesis and their role in breast cancer progression [27], our results add a new dimension by demonstrating a crosstalk between proteolysis and miRNAs, and a potential regulatory role of KLK5 in controlling the expression of miRNA networks which affect target Extracellular matrix (ECM) molecule interactions

Summary

Introduction

Breast cancer is the most common cancer and the leading cause of death of cancer for women [1]. The human kallikrein-related peptidases (KLK) are expressed in various tissues including breast, ovary, prostate, and kidney [5]. They have been found to be dysregulated in different cancers [6]. KLK5 has been reported to be dysregulated in breast cancer with its over-expression is indicative of good prognosis . [7,8,9,10] We recently showed that KLK5 exerts tumour suppressive effects by inhibiting the mevalonate pathway in breast cancer cells, inhibiting the activation of signaling oncoproteins due to inhibited prenylation [11]. Other molecular mechanisms by which KLK5 influences tumour behaviour are yet to be elucidated

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Results

Conclusion