Abstract:
Despite advances in cancer research, conventional breast cancer therapy still has disadvantages. Molecular targeted therapy has recently emerged as a promising treatment regime because of its potential for improved specificity and reduced toxicity. Therefore, discovering novel targets is a crucial task, and a principal aim of this study. I identified novel oncogenes SHON (secreted hominoid-specific oncogene) and GT27 and examined their role in breast cancer progression. Both SHON and GT27 were selected from the “secreted protein discovery initiative (SPDI), a large scale effort to discover novel secreted and/or transmembrane proteins” based on the completion of human genome sequencing. To investigate the function of SHON in mammary carcinoma cells, stably transfected cell lines were generated by transfecting SHON expressing plasmids. Forced expression of SHON in MCF-7 cells significantly increased cell proliferation, migration, invasion and anchorage independent growth. Moreover, forced expression of SHON in MCF-7 cells increased tumour volume in a xenograft model and immunohistochemistry of human breast cancer tissues revealed that expression of SHON is positively correlated with the higher stage and metastasis of breast cancer. Conversely, depletion of endogenous SHON by small interfering RNAs clearly reduced cell proliferation, migration, invasion and anchorage independent growth. Forced expression of SHON in T47D cells also enhanced oncogenicity of the mammary carcinoma cells. When changes in mRNA expression level of key genes regulating cell proliferation and invasion were examined by real time PCR, forced expression of SHON increased BCL-2 and NF-кB mRNA expression. Western blot analysis showed that SHON over-expression in MCF-7 cells resulted in increased expressions of BCL-2 and components of NF-кB signaling pathway. Treatment of BCL-2 or NF-кB inhibitors, significantly attenuated SHON stimulated anchorage-independent growth in soft agar as well as three-dimensional growth in Matrigel, indicating that the oncogenicity of SHON is mediated by BCL-2 and NF-кB. To investigate the oncogenic function of another novel gene GT27 in mammary carcinoma, stable cell lines were generated by transfecting GT27 expression plasmids in MCF-7 cells. Forced expression of GT27 in MCF-7 cells promoted cell number, evasion of apoptosis, anchorage independent growth and cell migration, but not invasion. Further investigation on novel oncogenes may result in discovery of a useful therapeutic target for treating breast cancer and SHON and GT27 may be promising candidates.