The multiple roles of Id-1 in cancer progression

Id-1 (Inhibitor of differentiation/DNA binding) is a member of the helix–loop–helix protein family expressed in actively proliferating cells. It regulates gene transcription by heterodimerization with the basic helix–loop–helix transcription factors and therefore inhibits them from DNA binding and transactivation of their target genes. Early studies showed that Id-1 functions mainly as a regulator in cellular differentiation of the muscle cells. The oncogenic role of Id-1 was revealed recently by the finding that Id-1 expression was able to induce cancer cell growth and promote cell survival. In addition, Id-1 protein was frequently overexpressed in over 20 types of cancer, supporting its role in the tumorigenesis of a wide range of tissues. However, the fact that Id-1 was able to activate multiple pathways involved in tumor progression suggests that Id-1 may in addition function in promotion of tumor development. For example, overexpression of Id-1 was found to induce expression of MT1-MMP protein, leading to invasion of breast cancer cells. A close association between Id-1 expression and angiogenesis has also been demonstrated recently in both normal and cancer cells. Accordingly, in prostate cancer cells, expression of Id-1 was able to activate EGF-R and nuclear factor-κB activities and resulted in progression to androgen independence. In addition, in both nasopharyngeal carcinoma and prostate cancer cells, Id-1 expression was found to protect the cells from chemotherapeutic drug-induced apoptosis through regulation of the Raf-1/MAPK and JNK pathways. This review will discuss recent evidence supporting the role of Id-1 in tumor progression and the mechanisms involved.