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PDZ-Binding Kinase/T-LAK Cell-Originated Protein Kinase, a Putative Cancer/Testis Antigen with an Oncogenic Activity in Breast Cancer

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PDZ-Binding Kinase/T-LAK Cell-Originated Protein Kinase, a Putative Cancer/Testis Antigen with an Oncogenic Activity in Breast Cancer Research Article PDZ-Binding Kinase/T-LAK Cell-Originated Protein Kinase, a Putative Cancer/Testis Antigen with an Oncogenic Activity in Breast Cancer Jae-Hyun Park, Meng-Lay Lin, Toshihiko Nishidate, Yusuke Nakamura, and Toyomasa Katagiri Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan Abstract to discover candidate target molecules for development of Breast cancer is one of the most common cancers among diagnosis and treatment of cancer (2). Through genome- women. To discover molecular targets that are applicable for wide expression analysis, we have isolated a number of oncogenes development of novel breast cancer therapy, we previously did that were involved in development and/or progression of genome-wide expression profile analysis of 81 breast cancers hepatocellular carcinomas (3, 4), synovial sarcomas (5, 6), and found dozens of genes that were highly and commonly and renal cell carcinomas (7). Such molecules are considered to up-regulated in breast cancer cells. Among them, we here be good candidate molecules for development of new therapeutic focused on one gene that encodes PDZ-binding kinase/T-LAK modalities. cell-originated protein kinase (PBK/TOPK), including a kinase Because cytotoxic drugs often cause severe adverse reactions, it domain. Northern blot analyses using mRNAs of normal is obvious that thoughtful selection of novel target molecules on the basis of well-characterized mechanisms of action should be human organs, breast cancer tissues, and cancer cell lines indicated this molecule to be a novel cancer/testis antigen. very helpful to develop effective anticancer drugs with the Reduction of PBK/TOPK expression by small interfering RNA minimum risk of side effects. Toward this goal, we previously did resulted in significant suppression of cell growth probably due the expression profile analysis of 81 breast cancers (8) and 29 to dysfunction in the cytokinetic process. Immunocyto- normal human tissues (9). Among the genes up-regulated in breast chemical analysis with anti-PBK/TOPK antibody implicated cancers, we focused on PDZ-binding kinase/T-LAK cell-originated a critical role of PBK/TOPK in an early step of mitosis. PBK/ protein kinase (PBK/TOPK), which is significantly overexpressed in TOPK could phosphorylate histone H3 at Ser10 in vitro and the great majority of breast cancer cases examined. PBK/TOPK was in vivo, and mediated its growth-promoting effect through first identified as a Dlg1-interacting protein by yeast two-hybrid histone H3 modification. Because PBK/TOPK is the cancer/ screening and characterized as a mitotic kinase with PDZ-binding testis antigen and its kinase function is likely to be related to motif at COOH terminus (10). PBK/TOPK was also identified by the its oncogenic activity, we suggest PBK/TOPK to be a promising other group as a mitogen-activated protein kinase (MAPK) kinase (MAPKK)–like protein kinase (11). molecular target for breast cancer therapy. (Cancer Res 2006; Cancer/testis antigens can be defined by predominant expres- 66(18): 9186-95) sion in various types of cancer and undetectable expression in normal tissues except germ cells in testis. To date, 44 distinct Introduction cancer/testis antigen families have been identified with particular Breast cancer is one of the most common cancers worldwide attention as potential targets for tumor immunotherapy (12). It has and has been significantly increasing (1). To reduce the mortality been reported that various cancer/testis antigens were expressed rate and to make the quality of life to the patients better, various relatively commonly in breast cancers, suggesting their potentials approaches, including early detection with mammography and for development of targeted therapy for breast cancer (13). Indeed, development of molecular-targeted therapeutic drugs, such as some of cancer/testis antigens, like NY-ESO-1 and NY-BR-1, are tamoxifen and trastuzumab, have been taken. Due to such efforts, applied as cancer vaccines in early clinical trials for breast cancer the mortality rates in Western societies have been improved, but patients (14). at present the very limited treatment options can be available to Here, we report overexpression of PBK/TOPK in the great patients at an advanced stage, particularly those with hormone- majority of breast cancer cells and that its kinase activity is likely to independent type. Hence, novel molecular-targeted drugs to play an important role in mammary carcinogenesis. Furthermore, provide better management to such patients are still eagerly the fact that PBK/TOPK expression pattern as the cancer/testis expected. antigen suggests PBK/TOPK to be a promising molecular target for cDNA microarray has been used as effective tools to analyze breast cancer therapy through cancer vaccine–mediated immuno- expression patterns of thousands of genes simultaneously. therapy and/or inhibition of PBK/TOPK–specific kinase function. Comparison of genome-wide expression profiles between cancers and normal cells by cDNA microarray provides useful information Materials and Methods Breast cancer cell lines and clinical samples. Human breast cancer cell lines BT-20, HCC1937, MCF-7, MDA-MB-435 S, SKBR3, T47D, and YMB1, Requests for reprints: Toyomasa Katagiri, Laboratory of Molecular Medicine, as well as immortalized human mammary cell-line HBL100, are purchased Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 from American Type Culture Collection (Rockville, MD), and cultured under Shirokanedai, Minato-ku, 108-8639 Tokyo, Japan. Phone: 81-3-5449-5374; Fax: 81-3- the recommendations of their respective depositors. Human mammalian 5449-5406; E-mail: [email protected]. I2006 American Association for Cancer Research. epithelial cell (HMEC) is purchased from Cambrex Bio Science (Walkers- doi:10.1158/0008-5472.CAN-06-1601 ville, MD). HBC4, HBC5, and MDA-MB-231 cell lines are kind gifts from Cancer Res 2006; 66: (18). September 15, 2006 9186 www.aacrjournals.org Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2006 American Association for Cancer Research. PBK/TOPK as a Novel Molecular Target for Breast Cancer Dr. Yamori (Division of Molecular Pharmacology, Cancer Chemotherapy for 15 minutes, and rendered permeable with PBS (À) containing 0.1% Center, Japanese Foundation for Cancer Research, Tokyo, Japan). All cells Triton X-100 at 4jC for 2.5 minutes. Subsequently, the cells were covered were cultured in appropriate medium, i.e., RPMI 1640 (Sigma-Aldrich, St. with 3% bovine serum albumin in PBS (À)at4jC for 12 hours to block Louis, MO) for HBC4, HBC5, HCC1937, T47D, and YMB1 (with 2 mmol/L nonspecific hybridization followed by incubation with a mouse anti- L-glutamine); DMEM (Sigma-Aldrich) for HBL100; EMEM (Sigma-Aldrich) PBK/TOPK monoclonal antibody (BD Biosciences) diluted at 1:100. After for BT-20 and MCF-7 (with 0.01 mg/mL insulin); McCoy (Sigma-Aldrich) for washing with PBS (À), the cells were stained by an Alexa 594–conjugated SKBR3 (with 1.5 mmol/L L-glutamine); L-15 (Roche, Basel, Switzerland) for anti-mouse secondary antibody (Molecular Probes, Eugene, OR) diluted at MDA-MB-231 and MDA-MB-435S; MEGM (Cambrex Bio Science) for HMEC. 1:1,000. Nuclei were counterstained with 4¶,6¶-diamidine-2¶-phenylindole Each medium was supplemented with 10% fetal bovine serum (Cansera dihydrochloride (DAPI). Fluorescent images were obtained under a TCS SP2 International, Etobicoke, Ontario, Canada) and 1% antibiotic/antimycotic AOBS microscope (Leica, Tokyo, Japan). To examine phosphorylated solution (Sigma-Aldrich). MDA-MB-231 and MDA-MB-435S cells were histone H3 at Ser10, the protein was detected by phosphorylated histone 10 maintained at 37jC in atmosphere of humidified air without CO2. Other H3 (Ser )–specific rabbit polyclonal antibody (Cell Signaling Technologies, cell lines were maintained at 37jC in atmosphere of humidified air with 5% Beverly, MA). CO2. Tissue samples from surgically resected breast cancers and their Immunohistochemical staining. Expression patterns of PBK/TOPK corresponding clinical information were obtained from Department of protein in breast cancer and normal tissues were investigated as described Breast Surgery, Cancer Institute Hospital, Tokyo, after obtaining written previously (7) by using anti-PBK/TOPK mouse monoclonal antibody (BD informed consent. Biosciences). For investigation of normal organs, we purchased commer- Semiquantitative reverse transcription-PCR analysis. We extracted cially available tissue sections of heart, lung, liver, kidney, and testis total RNA from each of breast cancer clinical samples and from (Biochain). Briefly, paraffin-embedded specimens were treated with xylene microdissected cells, respectively, and then did T7-based amplification and ethanol, and were blocked by protein-blocking reagent (DakoCytoma- and reverse transcription as described previously (15). We prepared tion, Carpinteria, CA). The monoclonal antibody in antibody-diluted appropriate dilutions of each single-stranded cDNA for subsequent PCR solution (1:50) was added and then stained with substrate-chromogen by monitoring the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (DAKO liquid 3,3¶-diaminobenzidine chromogen, DakoCytomation). Finally, as a quantitative internal control. The PCR primer sequences were tissue specimens were stained with hematoxylin to discriminate nucleus 5¶-CGACCACTTTGTCAAGCTCA-3¶ and 5¶-GGTTGAGCACAGGGTACTT- from cytoplasm. TATT-3¶
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