Overexpression of Glycosylphosphatidylinositol (GPI) Transamidase Subunits Phosphatidylinositol Glycan Class T and/or GPI Anchor Attachment 1 Induces Tumorigenesis and Contributes to Invasion in Human Breast Cancer

Guojun Wu,Susanne M Gollin,Motonobu Osada,Elizabeth Mambo,Feng Wu,David Sidransky,Aditi Chatterjee,Joseph A Califano,Edward A Ratovitski,Saraswati Sukumar,Ethel Rubin,Xiaofei Chang,Zhongmin Guo,Xin Huang,Barry Trink,Myoung Sook Kim,Chulso Moon

doi:10.1158/0008-5472.can-06-0506

Abstract

Based on the oncogenic role of phosphatidylinositol glycan (PIG) class U in human tumors, we explored the role of two additional subunits of the glycosylphosphatidylinositol (GPI) transamidase complex in human breast cancer. We found that PIG class T (PIG-T) and GPI anchor attachment 1 (GPAA1) were overexpressed in breast cancer cell lines and primary tumors. Forced expression of PIG-T and GPAA1 transformed NIH3T3 cells in vitro and increased tumorigenicity and invasion of these cells in vivo. Suppression of PIG-T expression in breast cancer cell lines led to inhibition of anchorage-independent growth. Moreover, we found that PIG-T and GPAA1 expression levels positively correlated with paxillin phosphorylation in invasive breast cancer cell lines. Furthermore, suppression of PIG-T and GPAA1 expression led to a decrease in paxillin phosphorylation with a concomitant decrease in invasion ability. These results suggest that the GPI transamidase complex is composed of a group of proto-oncogenes that individually or as a group contribute to breast cancer growth. This aberrant growth is mediated, at least partially, by phosphorylation of paxillin, contributing to invasion and progression of breast cancer.

Highlights

Cancer is a disease caused by accumulation of multiple genetic and epigenetic alterations in two main categories of genes, tumor suppressor genes and oncogenes [1]
We recently found that phosphatidylinositol glycan (PIG) class U (PIG-U), a component of the glycosylphosphatidylinositol (GPI) transamidase complex located on chromosomal band 20q11, is amplified and overexpressed in bladder cancer cell lines and primary tumors and causes malignant transformation in vitro and in vivo [18]
We found that the expression level of phosphorylated paxillin, E-cadherin, integrin-h1, but not fusin, matrix metalloproteinase 2 (MMP2), and Brk, correlated with the protein expression status of both PIG class T (PIG-T) and GPI anchor attachment 1 (GPAA1) in these two breast cancer cells (Fig. 5A)

Summary

Introduction

Cancer is a disease caused by accumulation of multiple genetic and epigenetic alterations in two main categories of genes, tumor suppressor genes and oncogenes [1]. Chromosomal translocation and gene mutations, which will lead to inactivation of tumor suppressor genes and activation of oncogenes, are common genetic alterations. ERBB2 at the 17q12 amplicon [5], c-MYC at the 8q24 amplicon [6], CCND1 at the 11q13 amplicon [7, 8], ZNF217 and CYP24 at the 20q13.2 amplicon [9,10,11], and PPM1D and TBX2 at the 17q23 amplicon [12,13,14,15] Among these amplicons, 8q24, 20q11-13, and 17q23 are frequently altered in breast cancer, the most common cause of cancer death in women in the Western world [16, 17]

Methods

Results

Conclusion