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

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

Profiling the expression pattern of GPI transamidase complex subunits in human cancer

“…Of them, 42% showed amplification of PIG-U, 13% showed amplification of PIG-T and only 11.6% showed increased copy number of GPAA1. 9 Here, the fourth subunit, GPI8, showed higher accumulation in 64% of ovarian cancer and 67% of uterine cancer cases. The fifth subunit, PIG-S, did not show any significant deregulation in expression levels in breast, ovary or uterine cancers.…”

“…Wu et al 9 have recently reported on the amplification of three of the GPIT subunits in primary breast cancer cases. Of them, 42% showed amplification of PIG-U, 13% showed amplification of PIG-T and only 11.6% showed increased copy number of GPAA1.…”

“…We recently demonstrated that PIG-T, GPAA1 and PIG-U are overexpressed in both human breast cancer cell lines and tumors and show gain of copy number. 9 Further, we reported that PIG-T and GPAA1 induce tumorigenesis and contributes to invasion in human breast cancer. 9 Other reports also show that GPAA1 was one of the seven overexpressed genes in both hepatitis B and C virus-positive hepatocellular carcinomas, 10 and gene amplification of GPAA1 was significantly associated with poor cellular differentiation and poor prognosis of HCC.…”

“…9 Further, we reported that PIG-T and GPAA1 induce tumorigenesis and contributes to invasion in human breast cancer. 9 Other reports also show that GPAA1 was one of the seven overexpressed genes in both hepatitis B and C virus-positive hepatocellular carcinomas, 10 and gene amplification of GPAA1 was significantly associated with poor cellular differentiation and poor prognosis of HCC. 11 Thus from these reports it can be speculated that components of the GPIT complex may function either independently or as a functional group of oncogenes in cancer.…”

Discovery of non-ETS gene fusions in human prostate cancer using next-generation RNA sequencing

“…PIGU is overexpressed in bladder cancers and has been proposed as an oncogene in bladder (Guo et al 2004) and breast cancer (Wu et al 2006). PIGU protein has been found to be upregulated in prostate cancer (Nagpal et al 2008).…”