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GPI) Transamidase Subunits Phosphatidylinositol Glycan Class T And/Or GPI Anchor Attachment 1Induces Tumorigenesis and Contributes to Invasion in Human Breast Cancer

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GPI) Transamidase Subunits Phosphatidylinositol Glycan Class T And/Or GPI Anchor Attachment 1Induces Tumorigenesis and Contributes to Invasion in Human Breast Cancer Research Article Overexpression of Glycosylphosphatidylinositol (GPI) Transamidase Subunits Phosphatidylinositol Glycan Class T and/or GPI Anchor Attachment 1Induces Tumorigenesis and Contributes to Invasion in Human Breast Cancer Guojun Wu,1,5 Zhongmin Guo,1 Aditi Chatterjee,1 Xin Huang,6 Ethel Rubin,2 Feng Wu,3 Elizabeth Mambo,1 Xiaofei Chang,1 Motonobu Osada,1 Myoung Sook Kim,1 Chulso Moon,1 Joseph A. Califano,1 Edward A. Ratovitski,4 Susanne M. Gollin,6 Saraswati Sukumar,2 David Sidransky,1 and Barry Trink1 1Department of Otolaryngology-Head and Neck Surgery, 2Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, 3Division of Gastroenterology, Department of Medicine, and 4Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; 5Breast Cancer Program, Karmanos Cancer Institute, Department of Pathology, Wayne State University, Detroit, Michigan; and 6Department of Human Genetics, University of PittsburghGraduate School of Public Health, Oral Cancer Center at the University of Pittsburgh, Pittsburgh, Pennsylvania Abstract ERBB2 at the 17q12 amplicon (5), c-MYC at the 8q24 amplicon (6), Based on the oncogenic role of phosphatidylinositol glycan CCND1 at the 11q13 amplicon (7, 8), ZNF217 and CYP24 at the (PIG) class U in human tumors, we explored the role of two 20q13.2 amplicon (9–11), and PPM1D and TBX2 at the 17q23 additional subunits of the glycosylphosphatidylinositol (GPI) amplicon (12–15). Among these amplicons, 8q24, 20q11-13, and transamidase complex in human breast cancer. We found that 17q23 are frequently altered in breast cancer, the most common PIG class T(PIG-T)and GPI anchor attachment 1 (GPAA1) were cause of cancer deathin women in theWestern world (16, 17). overexpressed in breast cancer cell lines and primary tumors. We recently found that phosphatidylinositol glycan (PIG) class Forced expression of PIG-Tand GPAA1 transformed NIH3T3 U (PIG-U), a component of the glycosylphosphatidylinositol (GPI) cells in vitro and increased tumorigenicity and invasion of transamidase complex located on chromosomal band 20q11, is these cells in vivo. Suppression of PIG-Texpression in breast amplified and overexpressed in bladder cancer cell lines and primary tumors and causes malignant transformation in vitro cancer cell lines led to inhibition of anchorage-independent in vivo growth. Moreover, we found that PIG-Tand GPAA1 expression and (18). The GPI anchor is one of many anchors that levels positively correlated with paxillin phosphorylation in mediate many membranous enzymes, receptors, differentiation invasive breast cancer cell lines. Furthermore, suppression of antigens, and other biologically active proteins bound to the PIG-Tand GPAA1 expression led to a decrease in paxillin phos- plasma membrane in unicellular and higher eukaryotes. It is phorylation with a concomitant decrease in invasion ability. essential for the expression of those proteins on the cell surface. These results suggest that the GPI transamidase complex is In eukaryotic cells, bothbiosynthesisof GPI precursors and post- composed of a group of proto-oncogenes that individually or translational protein modifications withGPI proceed in the as a group contribute to breast cancer growth. This aberrant endoplasmic reticulum (ER). The COOH-terminal GPI attachment growth is mediated, at least partially, by phosphorylation of signal peptide is split from the protein, and the resulting new paxillin, contributing to invasion and progression of breast COOH terminus is then combined to GPI precursors. These cancer. (Cancer Res 2006; 66(20): 9829-36) processes are all mediated by the GPI transamidase complex. At present, there are five subunits identified in the GPI trans- amidase complex [PIG class T (PIG-T), GPI anchor attachment 1 Introduction (GPAA1), GPI8, PIG class S (PIG-S), and PIG-U; refs. 19–21]. Cancer is a disease caused by accumulation of multiple genetic Although PIG-U is an oncogene in human bladder cancer, the and epigenetic alterations in two main categories of genes, tumor function of the other GPI transamidase subunits in human suppressor genes and oncogenes (1). Chromosomal translocation cancer has not been clarified. We found that, like PIG-U, both and gene mutations, which will lead to inactivation of tumor sup- GPAA1 and PIG-T are located on chromosomal regions that pressor genes and activation of oncogenes, are common genetic harbor gain of copy number in breast cancer. GPAA1 is located alterations. Another common genetic alteration in cancer is mani- on chromosomal region 8q24, and PIG-T is located on fested by genomic amplification and/or DNA copy number gain, chromosomal region 20q13.12 (22). We thus hypothesized that leading to the overexpression of oncogenes (2–4). Examples include individual subunits of the GPI transamidase complex might function either separately or as a functional group of oncogenes in breast cancer. Note: Supplementary data for this article are available at Cancer Research Online In the current study, we found overexpression and gain of (http://cancerres.aacrjournals.org/). copy number of PIG-T, GPAA1, and PIG-U in human breast Requests for reprints: David Sidransky and Barry Trink, Department of PIG-T Otolaryngology-Head and Neck Surgery, Head and Neck Cancer ResearchDivision, cancer cell lines and primary tumors. We also cloned and Johns Hopkins University School of Medicine, CRBII, 1550 Orleans St., Baltimore, MD GPAA1 and analyzed their tumorigenicity in vitro and in vivo.In 21231. Phone: 410-502-5153; Fax: 410-614-1411; E-mail: [email protected] or addition, we discovered that overexpression of GPI transamidase [email protected]. I2006 American Association for Cancer Research. subunits could induce tumor invasion possibly through activated doi:10.1158/0008-5472.CAN-06-0506 paxillin. www.aacrjournals.org 9829 Cancer Res 2006; 66: (20). October 15, 2006 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2006 American Association for Cancer Research. Cancer Research Materials and Methods Tumor xenografts. Cells (5 Â 106) were injected s.c. into athymic nude mice (CD-1-nuBR from Charles River, Wilmington, MA), and animals were Human breast cancer cell lines and tumors. The breast cancer cell killed 36 days after injection. Tumor size was measured eachweek, and lines examined, MDA-MB157, MDA-MB231, MDA-MB468, MCF7, and BT20, tumor volume (V) was estimated from length(L ) and width( W) using the were kindly provided by Drs. Nancy E. Davidson and Scott E. Kern (Johns following formula: V =(p /6)Â [(L + W)/2]3. Animal experiments were Hopkins University School of Medicine, Baltimore, MD) and Dr. Fergus J. conducted under protocol approved by the Central Animal Facility at the Couch (Mayo Clinic, Rochester, MN), whereas others were obtained from Johns Hopkins Medical Institute. the American Type Culture Collection (Manassas, VA). A total of 59 primary RNA interference constructs. RNA interference (RNAi) constructs were infiltrating ductal adenocarcinomas and 10 paired normal and tumor designed using the GeneSuppressor System. We designed two RNAi tissues were obtained from patients undergoing surgical treatment for constructs for GPAA1 and PIG-U and three RNAi constructs each for breast cancer at Johns Hopkins. Institutional Review Board approval was PIG-T (see Supplementary Data 2). For the negative control plasmid, a obtained for this research (04-09-21-02e). Each tumor contained >70% scrambled sequence is provided in the GeneSuppressor manual from tumor cells by H&E staining and was of high grade (Elston). Genomic DNA Imgenex (San Diego, CA; Supplementary Data 2). Forward and reverse was prepared using the proteinase K method followed by extraction with oligonucleotides (60 bp) were synthesized at Invitrogen. The oligonucleo- phenol-chloroform and precipitated with ethanol. Total RNA was extracted tides were then annealed and cloned into an IMG-8 (pSuppressorNeo) using Trizol reagent according to the manufacturer’s protocol (Invitrogen, vector at the XhoI and BamH sites. Correct constructs were picked after Carlsbad, CA). restriction digestion and subsequent sequencing. To check the effect of Quantitative real-time PCR. Specific primers and probes were designed different RNAi constructs, we transfected 1 Ag of different gene RNAi using Primer Express software (Applied Biosystems, Foster City, CA) to constructs or scrambled control RNAi construct into six-well dishplated PIG-T, PIG-U GPAA1 h amplify ,and genes and control -actin (see withbreast cancer cells. Expression was checkedby Western blot analysis. Supplementary Data 1). The samples were run in triplicate using pro- Double-stranded small interfering RNA (siRNA) targeting human paxillin, h tocol described by Mambo et al. (23). Primers and probes to -actin were control nontargeting siRNA1, and transfection reagent DharmaFECT 1 were run in parallel to standardize the input DNA. Standard curves were purchased from Dharmacon (Lafayette, CO). Sequence targeted by siRNA developed using serial dilutions of DNA extracted from MCF12A cells. Real- was selected using Dharmacon Smartdesign: paxillin, GTGTGGAGCCTTC- time PCR was run on the ABI 7900 Taqman (Applied Biosystems) accord- TTTGGT. ing to the manufacturer’s protocol. For measuring the expression level, we Western blot. This was done according to standard protocols. The did the reverse transcription reactions with a cDNA synthesis kit antibodies used included the following: paxillin (1:400; Cell Signaling, A A (Invitrogen), and 1 L of the total
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