A Pair of Prognostic Biomarkers in Triple-Negative Breast Cancer: KLK10 and KLK11 mRNA Expression

Abstract

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor patient prognosis and limited therapeutic options. A lack of prognostic biomarkers and therapeutic targets fuels the need for new approaches to tackle this severe disease. Extracellular matrix degradation, release, and modulation of the activity of growth factors/cytokines/chemokines, and the initiation of signaling pathways by extracellular proteolytic networks, have been identified as major processes in the carcinogenesis of breast cancer. Members of the kallikrein-related peptidase (KLK) family contribute to these tumor-relevant processes, and are associated with breast cancer progression and metastasis. In this study, the clinical relevance of mRNA expression of two members of this family, KLK10 and KLK11, has been evaluated in TNBC. For this, their expression levels were quantified in tumor tissue of a large, well-characterized patient cohort (n = 123) via qPCR. Although, in general, the overall expression of both factors are lower in tumor tissue of breast cancer patients (encompassing all subtypes) compared to normal tissue of healthy donors, in the TNBC subtype, expression is even increased. In our cohort, a significant, positive correlation between the expression levels of both KLKs was detected, indicating a coordinate expression mode of these proteases. Elevated KLK10 and KLK11 mRNA levels were associated with poor patient prognosis. Moreover, both factors were found to be independent of other established clinical factors such as age, lymph node status, or residual tumor mass, as determined by multivariable Cox regression analysis. Thus, both proteases, KLK10 and KLK11, may represent unfavorable prognostic factors for TNBC patients and, furthermore, appear as promising potential targets for therapy in TNBC.

MicroRNA-141-regulated KLK10 and TNFSF-15 gene expression in hepatoblastoma cells as a novel mechanism in liver carcinogenesis

“…In the same context, in colon cancer, miR-141 and miR-425-3p activate mutations in KRAS in Colorectal cancer (CRC) patients. Additionally, the miR-200 family binds to RASSF2 in the MAPK/ERK signaling pathway which support their oncogenic role 8 , 10 , 15 . Moreover, miR-141 can target the STAT4 gene expression, leading to liver cancer cell progression 41 .…”

“…Additionally, this was confirmed by direct binding interaction between the miR-200 family and RASSF2 9 . Notably, the kallikrein-related peptidase 10 (KLK 10) factor plays a pivotal role in tumorigenesis in both breast cancer and prostate cancer 10 . In addition, the KLK 10 overexpression in prostate cancer (PC) specifically in PC-3 cell line leads to decelerate tumor proliferation 11 .…”

KLK10 promotes the progression of KRAS mutant colorectal cancer via PAR1‐PDK1‐AKT signaling pathway

“…In addition, KLK10 overexpression is also frequently observed in ovarian cancer and is responsible for the rapid cancer growth (Luo et al, 2003; Shvartsman et al, 2003). Moreover, KLK10 promotes the development of trastuzumab and tamoxifen resistance in breast cancer and is associated with unfavorable prognosis of triple‐negative breast cancer (Liu et al, 2022; Luo et al, 2002; Wang et al, 2016). In gastric cancer, uterine serous papillary carcinoma, pancreatic ductal adenocarcinoma, and oral squamous cell carcinoma, KLK10 has been identified as an independent, unfavorable prognostic marker (Jiao, 2013; Pettus et al, 2009; Rückert et al, 2008; Santin et al, 2006).…”