Expression of human Kallikrein 14 (KLK14) in breast cancer is associated with higher tumour grades and positive nodal status

Abstract

Human kallikrein 14 (KLK14) is a steroid hormone-regulated member of the tissue kallikrein family of serine proteases, for which a prognostic and diagnostic value in breast cancer has been suggested. To further characterise the value of KLK14 as a breast tumour marker, we have carefully analysed KLK14 expression in normal breast tissue and breast cancer both on the RNA level by real-time RT-PCR (n ¼ 39), and on the protein level (n ¼ 127) using a KLK14-specific antibody for immunohistochemistry. We correlated KLK14 protein expression data with available clinico-pathological parameters (mean follow-up time was 55 months) including patient prognosis. KLK14 RNA expression as quantified by real-time RT-PCR was significantly more abundant in breast tumours compared to normal breast tissue (P ¼ 0.027), an issue that had not been clarified recently. Concordantly with the RNA data, cytoplasmic KLK14 protein expression was significantly higher in invasive breast carcinomas compared to normal breast tissues (P ¼ 0.003). Furthermore, KLK14 protein expression was associated with higher tumour grade (P ¼ 0.041) and positive nodal status (P ¼ 0.045) but was not significantly associated with shortened disease-free or overall patient survival time in univariate analyses. We conclude that KLK14 is clearly overexpressed in breast cancer in comparison to normal breast tissues and is positively associated with conventional parameters of tumour aggressiveness, but due to a missing association with survival times, the use of KLK14 immunohistochemistry as a prognostic marker in breast cancer is questionable.

Kallikrein-related peptidases (KLKs): a gene family of novel cancer biomarkers

“…KLK14 and KLK4 mRNA positivity is associated with high tumor grade and size (122,123) . In accordance with the mRNA data, strong immunohistochemical KLK14 staining of the malignant breast tumors is linked to aggressive phenotypes of the disease (124) .…”

Role of Pro-oncogenic Protein Disulfide Isomerase (PDI) Family Member Anterior Gradient 2 (AGR2) in the Control of Endoplasmic Reticulum Homeostasis

“…Recently, numerous studies demonstrated the elevated expression of AGR2 in various human preneoplasic states (30) and cancers including those of the esophagus (37), prostate (38 -41), pancreas (42), lung (43), breast (25,27,44), and biliary system (26), thus showing that it is a widely overexpressed protein in human carcinomas. This might indicate that several experimental and pathophysiological systems could be necessary to tackle the precise molecular and cellular functions of AGR2.…”

“…This protein, which contains a pseudo thioredoxin domain, is encoded by an estrogen receptor-responsive gene. AGR2 is found in various cancers to be overexpressed in precancerous states and is indicative of a bad prognosis (25)(26)(27)(28)(29)(30). However the molecular roles played by AGR2 remain unclear.…”

Expression and Functional Characterization of the Cancer-related Serine Protease, Human Tissue Kallikrein 14

“…Consequent to its secretion, KLK14 forms a constituent of seminal plasma (10) and sweat (14) and is present in its catalytically active form in the stratum corneum of the skin (13)(14)(15). Furthermore, aberrant KLK14 expression has been detected in patients with breast (7,10,11,16), ovarian (7,9,10), prostate (7,17), and testicular (7) cancers and peeling skin syndrome (18), at the tissue and/or serum level. Correlative clinical data have also linked elevated KLK14 mRNA expression with aggressive forms of breast (11,16) and prostate cancer (17) and with the prognosis of breast (16) and ovarian (9) cancer patients.…”

“…Subsequent studies demonstrated that the KLK14 gene is under steroid-hormone regulation (9,10) and is most highly expressed in the glandular epithelia of the breast (10,11) and prostate (8,10) and in the epidermis (i.e. stratum granulosum) and appendages (i.e.…”