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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

¹ Department of Otolaryngology-Head and Neck Surgery, ² Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, ³ Division of Gastroenterology, Department of Medicine, and ⁴ Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; ⁵ Breast Cancer Program, Karmanos Cancer Institute, Department of Pathology, Wayne State University, Detroit, Michigan; and ⁶ Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Oral Cancer Center at the University of Pittsburgh, Pittsburgh, Pennsylvania

Requests for reprints: David Sidransky and Barry Trink, Department of Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, CRBII, 1550 Orleans St., Baltimore, MD 21231. Phone: 410-502-5153; Fax: 410-614-1411; E-mail: dsidrans{at}jhmi.edu or btrink{at}jhmi.edu.

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. (Cancer Res 2006; 66(22): 9829-36) (Cancer Res 2006; 66(20): 9829-36)

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