Yousef G M, Scorilas A, Magklara A, Memari N, Ponzone R, Sismondi P, Biglia N, Abd Ellatif M, Diamandis E P
Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
Br J Cancer. 2002 Nov 18;87(11):1294-300. doi: 10.1038/sj.bjc.6600590.
Many kallikrein genes were found to be differentially expressed in various malignancies, and prostate specific antigen (encoded by the KLK3 gene) is the best tumour marker for prostate cancer. Prostate specific antigen has recently been shown to be an independent favourable prognostic marker for breast cancer. KLK15 is newly discovered kallikrein gene that is located adjacent to KLK3 on chromosome 19q13.4. KLK15 has 41% similarity to KLK3 and the encoded protein, hK15, can activate pro-prostate specific antigen. We studied the expression of KLK15 by real-time quantitative reverse transcriptase-polymerase chain reaction in 202 tissues from patients with breast carcinoma of various stages, grades and histological types. KLK15 expression was found to be a significant predictor of progression-free survival (hazard ratio of 0.41 and P=0.011) and overall survival (hazard ratio of 0.34 and P=0.009). When all other known confounders were controlled in the multivariate analysis, KLK15 retained its prognostic significance. Higher concentrations of KLK15 mRNA were found more frequently in node negative patients (P=0.042). No association was found between KLK15 expression and any other clinicopathological variable. Further, KLK15 is an independent prognostic factor of progression-free survival and overall survival in the subgroup of patients with lower grade and those with oestrogen receptor and progesterone receptor negative tumours in both univariate and multivariate analysis. KLK15 levels of expression were slightly higher (although not statistically significant) in the oestrogen receptor negative and progesterone receptor negative subgroups of patients. KLK15 is up-regulated by androgens in breast cancer cell lines. Time-course and blocking experiments suggest that this regulation is mediated through the androgen receptor.
许多激肽释放酶基因在各种恶性肿瘤中存在差异表达，前列腺特异性抗原（由KLK3基因编码）是前列腺癌最好的肿瘤标志物。最近研究表明，前列腺特异性抗原也是乳腺癌独立的有利预后标志物。KLK15是新发现的激肽释放酶基因，位于19号染色体q13.4上，与KLK3相邻。KLK15与KLK3有41%的相似性，其编码的蛋白hK15可激活前列腺特异性抗原原。我们采用实时定量逆转录-聚合酶链反应研究了202例不同分期、分级及组织学类型的乳腺癌患者组织中KLK15的表达情况。结果发现，KLK15表达是无进展生存期（风险比为0.41，P=0.011）和总生存期（风险比为0.34，P=0.009）的显著预测指标。在多变量分析中，当控制了所有其他已知混杂因素后，KLK15仍具有预后意义。在无淋巴结转移的患者中，KLK15 mRNA浓度较高更为常见（P=0.042）。未发现KLK15表达与任何其他临床病理变量之间存在关联。此外，在单变量和多变量分析中，KLK15是低分级以及雌激素受体和孕激素受体阴性肿瘤患者亚组无进展生存期和总生存期的独立预后因素。在雌激素受体阴性和孕激素受体阴性的患者亚组中，KLK15的表达水平略高（尽管无统计学意义）。在乳腺癌细胞系中，雄激素可上调KLK15的表达。时间进程和阻断实验表明，这种调节是通过雄激素受体介导的。
