A Novel Protease Homolog Differentially Expressed in Breast and Ovarian Cancer

Anisowicz, Anthony; Sotiropoulou, Georgia; Stenman, Göran; Mok, Samuel C.; Sager, Ruth

doi:10.1007/bf03401646

Cited by 196 publications

(200 citation statements)

References 37 publications

(24 reference statements)

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“…The most widely used marker, CA125, has shown merit in pilot screening studies and ovarian cancer management, but the sensitivity for early-stage disease before clinical detection remains questionable (Bast et al, 1998). We have previously identified by differential display a cDNA that is highly expressed in ovarian tumour (Anisowicz et al, 1996). Sequence analysis has shown that this novel protein belongs to the human kallikrein protein family.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously identified by differential display a cDNA sequence that is highly expressed in primary breast and ovarian tumour tissues and cell lines (Anisowicz et al, 1996). The encoded protein, which originally was named as protease M, shows strong homology to the human kallikrein (hK) family proteins (for a review see Schachter, 1980;) and has a revised nomenclature of kallikrein 6 (KLK6 for the gene and hK6 for the encoded protein).…”

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Characterisation of human kallikrein 6/protease M expression in ovarian cancer

Zhang

Huang

et al. 2004

Br J Cancer

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Kallikrein 6 (hK6, also known as protease M/zyme/neurosin) is a member of the human kallikrein gene family. We have previously cloned the cDNA for this gene by differential display and shown the overexpression of the mRNA in breast and ovarian primary tumour tissues and cell lines. To thoroughly characterise the expression of this kallikrein in ovarian cancer, we have developed a novel monoclonal antibody specific to hK6 and employed it in immunohistochemistry with a wide range of ovarian tumour samples. The expression was found elevated in 67 of 80 cases of ovarian tumour samples and there was a significant difference in the expression levels between normal and benign ovarian tissues and the borderline and invasive tumours (Po0.001). There was no difference of expression level between different subtypes of tumours. More significantly, high level of kallikrein 6 expression was found in many early-stage and low-grade tumours, and elevated hK6 proteins were found in benign epithelia coexisting with borderline and invasive tissues, suggesting that overexpression of hK6 is an early phenomenon in the development of ovarian cancer. Quantitative real-time reverse transcription -polymerase chain reactions also showed elevated kallikrein 6 mRNA expression in ovarian tumours. Genomic Southern analysis of 19 ovarian tumour samples suggested that gene amplification is one mechanism for the overexpression of hK6 in ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Characterisation of human kallikrein 6/protease M expression in ovarian cancer

Zhang

Huang

et al. 2004

Br J Cancer

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“…Previously called zyme (Little et al, 1997), protease M (Anisowicz et al, 1996), and neurosin (Yamashiro et al, 1997), kallikrein 6 is now the accepted name (Diamandis et al, 2000b). hK6 is a trypsin-like serine protease of unknown physiologic function that is secreted as a 223 amino acid protein.…”

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confidence: 99%

“…Investigations are proceeding as sensitive and specific assays measuring the gene expression or protein mass of each newly identified member of the kallikrein family become available. Tissue expression of the kallikreins examined to date appears to be down-regulated in aggressive forms of breast cancer (hK3 (PSA) (Levesque et al, 1998), hK10 (Liu et al, 1996;Goyal et al, 1998), hK13 (Yousef et al, 2000) and hK6 (Anisowicz et al, 1996)) and up-regulated in ovarian cancer (hK4 (Obiezu et al, 2002), hK10 (Luo et al, 2001), hK5 (Kim et al, 2001), hK8 (Magklara et al, 2001) and hK6 (Tanimoto et al, 2001)). …”

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Immunofluorometric quantitation and histochemical localisation of kallikrein 6 protein in ovarian cancer tissue: a new independent unfavourable prognostic biomarker

et al. 2002

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Human kallikrein 6 protein is a newly discovered human kallikrein. We determined the amount of human kallikrein 6 in extracts of 182 ovarian tumours and correlated specific activity (ng hK6 mg 71 total protein) with clinicopathological variables documented at the time of surgical excision and with outcome (progression free survival, overall survival) monitored over a median interval of 62 months. Thirty per cent of the tumours were positive for human kallikrein 6 (435 ng hK6 mg 71 total protein). Human kallikrein 6-specific immunohistochemical staining of four ovarian tissues that included benign, borderline and malignant lesions indicated a cytoplasmic location of human kallikrein 6 in tumour cells of epithelial origin, although the intensity of staining was variable. Tumour human kallikrein 6 (ng hK6 mg 71 total protein) was higher in late stage disease, serous histotype, residual tumour 41 cm and suboptimal debulking (41 cm) (P50.05). Univariate analysis revealed that patients with tumour human kallikrein 6 positive specific activity were more likely to suffer progressive disease and to die (hazard ratio 1.71 (P=0.015) and 1.88 (P=0.022), respectively). Survival curves demonstrated the same (P=0.013 and 0.019, respectively). Multivariate analysis revealed that human kallikrein 6 positivity was retained as an independent prognostic variable in several subgroups of patients, namely those with (low) grade I and II tumours (hazard ratio progression free survival 4.3 (P=0.027) and overall survival 4.1 (P=0.023)) and those with optimal debulking (hazard ratio progression free survival 3.8 (P=0.019) and overall survival 5.6 (P=0.011)). We conclude that tumour kallikrein 6 protein levels have utility as an independent adverse prognostic marker in a subgroup of ovarian cancer patients with otherwise apparently good prognosis.

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“…Many new reports have shown that various members of the kallikrein gene family are differentially regulated in cancer. Specifically, the stratum corneum chymotryptic enzyme (KLK7), neuropsin (KLK8) and zyme (KLK6) have been shown to be overexpressed in ovarian tumours (Anisowicz et al, 1996;Tanimoto et al, 1999;Underwood et al, 1999) while the normal epithelial cell-specific 1 gene (NES1; KLK10) is down-regulated (Liu et al, 1996;Goyal et al, 1998).…”

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Human kallikrein gene 5 (KLK5) expression is an indicator of poor prognosis in ovarian cancer

et al. 2001

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Summary Kallikrein gene 5 (KLK5, also known as KLK-L2), located on chromosome 19q13.4, is one of the newly identified members of the kallikrein gene family, which is a subgroup of the serine protease enzyme family. In normal human tissues, KLK5 is highly expressed in skin, mammary gland and testis. Preliminary RT-PCR analysis has indicated that KLK5 is expressed in a subset of ovarian tumours. We have thus hypothesized that KLK5 may be a new prognostic indicator in ovarian cancer. We have examined the mRNA expression of KLK5 in 142 malignant ovarian tissues. Tumours were pulverized, total RNA was extracted, and cDNA was prepared by reverse transcription. KLK5 was amplified by PCR using gene specific primers, and the identity of the PCR product was verified by sequencing. Ovarian tissues were then classified as KLK5 positive or negative, based on ethidium bromide staining of the PCR product on agarose gels. KLK5 was found to be highly expressed in 58/142 (41%) of ovarian cancer samples while its level of expression was very low in normal ovarian tissues. We found a strong positive relation between KLK5 expression and tumour grade (P = 0.006) and disease stage (P = 0.027). Univariate survival analysis revealed that patients with ovarian tumours positive for KLK5 expression had an increased risk for relapse and death (P = 0.018 and 0.022, respectively). In multivariate analysis, KLK5 expression showed independent prognostic value only in the subset of tumours with lower grade disease (grades I and II). We conclude that KLK5 expression is associated with more aggressive forms of epithelial ovarian carcinoma and has indepdent prognostic value in low grade tumours. 643-650 © 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2000.1649, available online at http://www.idealibrary.com on http://www.bjcancer.comIn the present study, we have evaluated KLK5 mRNA expression in relation to patient survival and other clinicopathologic variables in epithelial ovarian carcinoma. Our results demonstrate that KLK5 is an independent prognostic marker of poor prognosis in a subset of patients with grade I/II tumours. MATERIALS AND METHODS Ovarian cancer specimens and patients142 consecutive patients with epithelial ovarian carcinoma were included in this study, with ages ranging from 25 to 80 with a median of 59 years. Patients underwent surgery and treatment for primary ovarian carcinoma at the Department of Obstetrics and Gynecology, Gynecologic Oncology Unit, University of Turin, Turin, Italy between July, 1991 and April, 1999. Follow-up information (median follow-up period 48 months) was available for 138 patients, among whom 83 (60%) have relapsed and 55 (40%) died. Of the 142 ovarian adenocarcinomas, for which histological diagnosis was available, 64 (45%) were serous papillary, 26 (18%) endometrioid, 22 (16%) undifferentiated, 12 (8%) clear cell, 11 (8%) mucinous, 6 (4%) Mullerian and 1 (1%) was unclassified. Due to the relatively small sample size, the clear cell, mucinous and Mullerian types were combined into one category...

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A Novel Protease Homolog Differentially Expressed in Breast and Ovarian Cancer

Abstract: Protease M expression (mRNA) may be a useful marker in the detection of primary mammary carcinomas, as well as primary ovarian cancers. Other medical applications are also likely, based on sequence relatedness to trypsin and PSA.

Cited by 196 publications

References 37 publications

Characterisation of human kallikrein 6/protease M expression in ovarian cancer

Characterisation of human kallikrein 6/protease M expression in ovarian cancer

Immunofluorometric quantitation and histochemical localisation of kallikrein 6 protein in ovarian cancer tissue: a new independent unfavourable prognostic biomarker

Human kallikrein gene 5 (KLK5) expression is an indicator of poor prognosis in ovarian cancer

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