Biochemical pathways mediated by KLK6 protease in breast cancer

Abstract

Kallikrein‐related peptidase 6 (KLK6) is a serine protease normally expressed in mammary tissue and aberrantly regulated in breast cancer. At physiological levels, KLK6 functions as a suppressor of breast cancer, while its aberrant overexpression (> 50‐fold higher than normal) is characteristic of a subset of breast cancers and has been linked to accelerated growth of primary breast tumors in severe combined immunodeficiency mice (Pampalakis et al. Cancer Res 2009, 69, 3779). Here, we investigated the molecular mechanisms underlying the concentration‐dependent functions of KLK6 by comparing MDA‐MB‐231 stable transfectants expressing increasing levels of KLK6 in in vitro and in vivo tumorigenicity assays (soft agar, xenograft growth, tail vein metastasis). Quantitative proteomics was applied to identify proteins that are altered upon re‐expression of KLK6 in MDA‐MB‐231 at normal or constitutive levels. Overexpression of KLK6 is associated with increased metastatic ability of breast cancer cells into lungs, increased expression of certain S100 proteins (S100A4, S100A11) and keratins (KRT), and downregulation of the apoptosis‐related proteases CASP7 and CASP8, and RABs. On the other hand, KLK6 re‐expression at physiological levels leads to inhibition of lung metastases associated with suppression of S100 proteins (S100A4, S100A10, S100A13, S100A16) and induced CASP7 and CASP8 expression. As this is the first report that KLK6 expression is associated with S100 proteins, caspases, RABs, and KRTs, we validated this finding in clinical datasets. By integrating proteomics and microarray data from breast cancer patients, we generated two composite scores, KLK6 + S100B‐S100A7 and KLK6 + S100B‐S100A14‐S100A16, to predict long‐term survival of breast cancer patients. We present previously unknown pathways implicating KLK6 in breast cancer. The findings promise to aid our understanding of the functional roles of KLK6 in breast cancer and may yield new biomarkers for the cancer types in which KLK6 is known to be aberrantly upregulated.

Biomarkers of tumor invasiveness in proteomics (Review)

“…Notably, although S100B was not detected in the data described in the present review, a recent study based on an integrative analysis of transcriptomic and proteomic data of MCF7 cells submitted to acid adaptation reported high expression levels of both S100B and S100A6 in the course of EMT process affecting breast cancer cells (316). Additionally, proteomics and microarray data from breast cancer patients have revealed a shorter long-term survival in two subsets of patients with a combined high expression of S100B, kallikrein and S100A7 or S100A14 -S100A16 (317).…”

Landscape Analysis of Matrix Metalloproteinases Unveils Key Prognostic Markers for Patients With Breast Cancer

“…6) Abnormal overexpression of human kallikrein-related peptidase 6 (KLK6) among serine peptidases is one of the characteristics of a subset of breast cancer. Pampalakis’ experiments ( Pampalakis et al, 2019 ) showed that its overexpression was related to the increased ability of breast cancer cells to metastasize to the lung, the increased expression of certain S100 proteins and keratins, and the down-regulation of apoptosis-related proteases 6. Feng et al (2016) ( Feng et al, 2016 ) used the immunohistochemical SP method to detect the expression of aminopeptidase in 80 cases, and found that the positive expression rate of aminopeptidase in breast cancer was much higher than that of normal breast tissue adjacent to cancer.…”

Kallikrein-Related Peptidase 6 (KLK6) as a Contributor toward an Aggressive Cancer Cell Phenotype: A Potential Role in Colon Cancer Peritoneal Metastasis

“…In addition, many studies have shown that aberrant expression of KLK6 in human malignancies, including colon cancer, is often regulated by microRNAs interactions [ 17 , 26 , 42 ]. Moreover, DNA methylation in the proximal promoter has been shown to repress KLK6 expression in breast cancer [ 43 ]. KLK6 upregulation in colon cancer may be rather influenced by other factors from the tumor microenvironment.…”