TY  - JOUR
AB  - Resistance to chemotherapy provides a major challenge in treatment of metastatic cancer. Prolonged exposure to almost any drug regimen leads to the formation of resistant subclones in almost all advanced solid tumors. Tumor heterogeneity because of intrinsic genetic instability is seen as one of the major contributing factors. In this work, we present evidence that genetic instability measured by mutation frequency is induced by treatment with the EGFR inhibitor afatinib or cisplatin in head and neck squamous cancer cells. We find that APOBEC3B and polymerase iota are upregulated, and inhibition of MEK1/2 by U0126 leads to downregulation on the protein level. Costimulation of afatnib and cisplatin with U0126 leads to a significantly lower mutation frequency. These findings may represent a molecular mechanism for dynamically controlling genetic instability during chemotherapy in head and neck squamous cell carcinoma (HNSCC) cancer cells.
AU  - Schulz, D.M.*
AU  - Piontek, G.*
AU  - Zissler, U.M.
AU  - Multhoff, G.*
AU  - Wirth, M.*
AU  - Pickhard, A.*
C1  - 63829
C2  - 51569
CY  - 40 White Oaks Ln, Madison, Wi 53711 Usa
SP  - 5581-5590
TI  - MEK1/2 regulates APOBEC3B and polymerase iota-induced mutagenesis in head and neck cancer cells.
JO  - Am. J. Cancer Res.
VL  - 11
IS  - 11
PB  - E-century Publishing Corp
PY  - 2021
ER  - 

TY  - JOUR
AB  - 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.
AU  - Geng, X.*
AU  - Babayeva, L.*
AU  - Walch, A.K.
AU  - Aubele, M.
AU  - Gross, E.*
AU  - Kiechle, M.*
AU  - Bronger, H.*
AU  - Dreyer, T.*
AU  - Magdolen, V.*
AU  - Dorn, J.*
C1  - 59870
C2  - 48953
CY  - 40 White Oaks Ln, Madison, Wi 53711 Usa
SP  - 1785-1792
TI  - High levels of KLK7 protein expression are related to a favorable prognosis in triple-negative breast cancer patients.
JO  - Am. J. Cancer Res.
VL  - 10
IS  - 6
PB  - E-century Publishing Corp
PY  - 2020
ER  - 

TY  - JOUR
AB  - Members of the human kallikrein-related peptidase (KLK) family, including KLK5, have been reported to play an important role in ovarian cancer progression. In the present study, we assessed KLK5 protein expression in ovarian cancer tissues by immunohistochemistry (IHC) and ELISA, and analyzed its association with clinicopathologic parameters and disease outcome in 95 patients with advanced ovarian cancer FIGO stage III/IV. KLK5 immunoexpression was evaluated in ovarian cancer tissue microarrays by IHC using a manual semiquantitative scoring system. KLK5 antigen levels were determined in ovarian cancer tumour tissue extracts by ELISA. KLK5 protein is expressed in ovarian cancer tissue by stromal and tumor cells. Mean KLK5 immunoscore values in tumor cells (KLK5-Tc; 5.7, range 0 to 12) were higher compared to stromal cells (KLK5-Sc; 1.2, range 0 to 9) but the correlation between KLK5-Tc and KLK5-Sc was rather low (rs = 0.34, P < 0.05). No significant associations of clinicopathological parameters with KLK5-Tc, KLK5-Sc, the combined overall score KLK5-Tc+Sc, or ELISA (KLK5-E) expression values were determined, except for KLK5-E protein expression with advanced age and high nuclear grade (G3). In univariate Cox regression analysis, elevated expression levels of KLK5-Sc are significantly linked with both prolonged overall survival (OS) (hazard ratio [HR] = 0.6, P = 0.046) and progression-free survival (PFS) (HR = 0.54, P = 0.032) of advanced ovarian cancer patients. KLK5-Tc and KLK5-Tc+Sc scores as well as the KLK5-E values were not associated with patients' outcome. In multivariable analysis, KLK5-Sc expression was found to be statistically significant for PFS. Patients with elevated KLK5-Sc had a two-fold lower risk of disease recurrence (HR = 0.53, P = 0.037) as compared to patients with low KLK5-Sc. For KLK5-Sc and OS, a trend towards statistical significance was observed (HR = 0.62, P = 0.077). These results indicate that KLK5 overexpression by stromal cells (KLK5-Sc) may be a positive modulator lowering aggressiveness of ovarian cancer.
AU  - Dorn, J.*
AU  - Yassouridis, A.*
AU  - Walch, A.K.
AU  - Diamandis, E.P.*
AU  - Schmitt, M.*
AU  - Kiechle, M.*
AU  - Wang, P.*
AU  - Drecoll, E.*
AU  - Schmalfeldt, B.*
AU  - Loessner, D.*
AU  - Kotzsch, M.*
AU  - Magdolen, V.*
C1  - 48389
C2  - 41025
SP  - 61-70
TI  - Assessment of kallikrein-related peptidase 5 (KLK5) protein expression in tumor tissue of advanced ovarian cancer patients by immunohistochemistry and ELISA: Correlation with clinical outcome.
JO  - Am. J. Cancer Res.
VL  - 6
IS  - 1
PY  - 2016
ER  -