Quantitative analysis of human kallikrein gene 14 expression in breast tumours indicates association with poor prognosis

Abstract

KLK14 (formerly known as KLK-L6) is a recently identified member of the human kallikrein gene family. This family harbours several genes aberrantly expressed in various cancers as well as established (PSA/hK3, hK2) and potential (hK6, hK10) cancer markers. Similar to other kallikrein genes, KLK14 was found to be regulated by steroid hormones, particularly androgens and progestins, in breast and ovarian cancer cell lines. Preliminary studies indicated that KLK14 is differentially expressed in breast, ovarian, prostatic and testicular tumours. Given the above, we determined the prognostic significance of KLK14 expression in breast cancer. We studied KLK14 expression in 178 histologically confirmed epithelial breast carcinomas by quantitative reverse transcription -polymerase chain reaction and correlated with clinicopathological variables (tumour stage, grade, histotype etc.) and with outcome (disease-free survival and overall survival), monitored over a median of 76 months. KLK14 mRNA levels ranged from 0 to 1219 arbitrary units in breast cancer tissues, with a mean+s.e. of 136+22. An optimal cutoff value of 40.5 arbitrary units was selected, to categorise tumours as KLK14-positive or negative. Higher concentrations of KLK14 mRNA were more frequently found in patients with advanced stage (III) disease (P=0.032). No statistically significant association was found between KLK14 and the other clinicopathological variables. KLK14 overexpression was found to be a significant predictor of decreased disease-free survival (hazard ratio of 2.31, P=0.001) and overall survival (hazard ratio of 2.21, P=0.005). Cox multivariate analysis indicated that KLK14 was an independent prognostic indicator of disease-free survival and overall survival. KLK14 also has independent prognostic value in subgroups of patients with a tumour size 42 cm and positive nodal, oestrogen receptor and progestin receptor status. We conclude that KLK14 expression, as assessed by quantitative reverse transcription -polymerase chain reaction, is an independent marker of unfavourable prognosis for breast cancer.

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

“…These data are in conflict to a recent RT-PCR study, which showed loss of KLK14 expression in 21 of 25 (84%) human breast cancer analysed ). However, our data are in agreement with another quantitative RT-PCR study that described much more abundant KLK14 expression (in 55 of 178 breast tumours) and a clear correlation of KLK14 expression and poor prognosis (Yousef et al, 2002a). The possible explanation for these disparities could be that our study and that of Yousef et al (2002a) used the more accurate quantitative RT-PCR technique.…”

“…However, our data are in agreement with another quantitative RT-PCR study that described much more abundant KLK14 expression (in 55 of 178 breast tumours) and a clear correlation of KLK14 expression and poor prognosis (Yousef et al, 2002a). The possible explanation for these disparities could be that our study and that of Yousef et al (2002a) used the more accurate quantitative RT-PCR technique. The present study is the first to analyse KLK14 protein expression in a large cohort of human breast cancer specimens in comparison to matching normal breast tissues using a recently characterised KLK14-specific antibody (Felber et al, 2005).…”

“…It remains to be focus of further study, whether KLK14 offers independent additional information in breast cancer or if KLK14 could be a potential target of specific therapy. An earlier study by Yousef et al (2002a) examined the prognostic value of KLK14 expression in 178 breast cancer on the RNA level and found that high KLK14 mRNA expression was associated with advanced stage (III) disease. KLK14 also was an independent predictor of decreased disease-free and overall survival.…”

“…KLK14 also was an independent predictor of decreased disease-free and overall survival. The cutoff value in this study (Yousef et al, 2002a) for KLK14 positive and negative tumours was defined by its ability to predict disease-free and overall survival and resulted in the definition of KLK14 positivity in 31% of breast tumours. In our study, we decided to use the median of KLK14 expression to delineate groups of low and high expression levels.…”

“…However, conflicting data have been obtained regarding the question whether KLK14 is overexpressed in breast tumours compared to normal breast tissue. Although one study reported loss of KLK14 expression in 21 of 25 analysed breast tumours in comparison to normal breast tissue , another study demonstrated abundant KLK14 expression in tumours and an association of high KLK14 expression with advanced disease (Yousef et al, 2002a). Thus, the presently available data leaves the question open whether KLK14 is a suitable biomarker for human breast cancer.…”