High levels of KLK7 protein expression are related to a favorable prognosis in triple-negative breast cancer patients.

In normal physiology, kallikrein-related peptidase 7 (KLK7), together with other members of the kallikrein-related peptidase family, is mainly involved in skin desquamation and keratinization processes. Moreover, expression of KLK7 was shown in various tumor types to be dysregulated and to correlate to patients' survival time. However, there are contradictory reports in breast cancer whether KLK7 represents an unfavorable or favorable prognostic biomarker. In the present study, we examined the prognostic value of KLK7 protein expression in triple-negative breast cancer (TNBC), determined by immunohistochemistry (IHC). A cohort encompassing 133 TNBC specimens, present on tissue microarrays, was analyzed. For quantification of the staining intensity, an automated digital IHC image analysis algorithm was applied. In both Kaplan-Meier and univariate Cox analyses, elevated KLK7 protein levels were significantly linked with prolonged overall survival (OS). In multivariable Cox analysis, addition of KLK7 immunoreactivity scores to the base model (including the clinical parameters age, tumor size, and nodal status) demonstrated that KLK7 protein expression remained as a statistically significant, independent parameter for prolonged OS. These results strongly indicate that KLK7 is a favorable prognostic biomarker in triple-negative breast cancer.

Prognostic value of kallikrein-related peptidase 12 (KLK12) mRNA expression in triple-negative breast cancer patients.

BACKGROUND: The serine protease KLK12 belongs to the human fifteen-member family of kallikrein-related peptidases. Differential expression accompanied by either increased or decreased enzymatic activity has been linked to several diseases including cancer. Triple-negative breast cancer (TNBC) represents a very aggressive subgroup of breast cancer with high tumor recurrence rates and poor patient prognosis. Here, we quantified the KLK12 mRNA expression levels in tumor tissue of TNBC patients and analyzed their prognostic value. METHODS: In the present study, KLK12 mRNA expression in tumor tissue of TNBC patients (n = 116) was determined by quantitative real-time PCR assay. The association of KLK12 mRNA levels with clinical parameters, and patients' outcome was analyzed using Chi-square tests, Cox regression models and Kaplan-Meier survival analysis. RESULTS: Positive, but low KLK12 mRNA levels were detected in about half of the cases (54 out of 116; 47%), the other samples were negative for KLK12 mRNA expression. No significant association was observed between KLK12 mRNA levels and clinicopathological variables (age, lymph node status, tumor size, and histological grade). In univariate Cox analyses, positive KLK12 mRNA expression was significantly associated with shortened disease-free survival (DFS; hazard ratio [HR] = 2.12, 95% CI = 1.19-3.78, p = 0.010) as well as overall survival (OS; HR = 1.91, 95% CI = 1.04-3.50, p = 0.037). In multivariable Cox analysis, including all clinical parameters plus KLK12 mRNA, the latter - together with age - remained an independent unfavorable predictive marker for DFS (HR = 2.33, 95% CI = 1.28-4.24, p = 0.006) and showed a trend towards significance in case of OS (HR = 1.80, 95% CI = 0.96-3.38, p = 0.066). CONCLUSIONS: Positive KLK12 expression is remarkably associated with shortened DFS and OS, suggesting that KLK12 plays a tumor-supporting role in TNBC.

Elevated tumor tissue protein expression levels of kallikrein-related peptidases KLK10 and KLK11 are associated with a better prognosis in advanced high-grade serous ovarian cancer patients.

Several members of the KLK family have been proposed to modulate various tumor-relevant processes. Previously, we have shown that in advanced high-grade serous ovarian cancer tissue high KLK11 mRNA levels were significantly associated with prolonged overall and progression-free patients' survival. Furthermore, KLK11 mRNA expression positively correlated with KLK10 mRNA. In the present study, we examined the prognostic value for both KLK10 and KLK11 on the protein expression level by immunohistochemistry (IHC). A cohort encompassing 159 patient tumor samples afflicted with advanced high-grade (FIGO III/IV) serous ovarian cancer, present on tissue microarrays (TMA), was analyzed. For estimation of KLK10 and KLK11 immunoreactivity, an automated digital IHC image analysis algorithm was selected to quantify the antibody staining intensity in the tissues via an immunoreactive score (IRS). In line with the results obtained by mRNA analysis, KLK10 protein expression values were significantly and positively correlated with KLK11 protein expression values. In Kaplan-Meier analyses, both elevated KLK10, KLK11, and the combination of KLK10 and KLK11 protein levels were significantly linked with prolonged overall survival (OS). The addition of KLK10, KLK11 or the KLK10+KLK11 combination IRS to the base model in multivariate Cox analysis demonstrated that high KLK11 and KLK10+KLK11 protein expression levels, apart from clinical parameters, remained favorable independent predictive markers for OS. In conclusion, in the present study, we have validated the coordinate expression of KLK10 and KLK11 in advanced high-grade serous ovarian cancer. Furthermore, both increased KLK10 and KLK11 protein expression is associated with favorable prognosis in this major ovarian cancer subtype. The combined KLK10+KLK11 marker performed even stronger than KLK10 or KLK11 alone.

Clinical relevance of kallikrein-related peptidase 9, 10, 11, and 15 mRNA expression in advanced high-grade serous ovarian cancer.

KLK9, 10, 11, and 15 may represent potential cancer biomarkers for evaluating ovarian cancer prognosis. In the present study, we selected a homogeneous cohort including 139 patients of advanced high-grade serous ovarian cancer (FIGO stage III/IV) and assessed the mRNA levels of KLK9, 10, 11, and 15 in tumor tissue by quantitative PCR. No significant associations of KLK9, 10, 11, and 15 mRNA with established clinical parameters (residual tumor mass, ascitic fluid volume) were found. Pronounced correlations between KLK10/KLK11 (rs = 0.647) and between KLK9/KLK15 (rs = 0.716) mRNA, but not between other combinations, indicate coordinate expression of distinct pairs of peptidases. In univariate Cox regression analysis, elevated KLK11 mRNA levels were significantly linked with prolonged overall survival (OS; p = 0.021) and progression-free survival (PFS; p = 0.008). KLK15 mRNA levels showed a trend towards significance in case of OS (p = 0.06); KLK9 and KLK10 mRNA expression levels were not associated with patients' outcome. In multivariable Cox analysis, KLK11 mRNA expression levels, apart from residual tumor mass, remained an independent predictive marker for OS (p = 0.007) and PFS (p = 0.015). Here, elevated KLK15 mRNA expression levels turned out to be significantly related to prolonged OS (p = 0.025) as well. High KLK11 but not the other KLK mRNA levels can be considered as strong independent favorable prognostic factor in this major ovarian cancer subtype.