Transcription Factors in Human Disease

Role of Runx2 in bone metastasis. Breast and prostate cancers preferentially spread to bone. Bone metastases cause extreme bone pain, fractures, nerve compression, and hypercalcaemia; the average survival time for patients is approximately two years. The development of therapies to combat bone metastasis largely depends on identifying new molecular targets for pharmacological intervention. What causes breast and prostate cancer cells to preferentially colonise the bone is largely unknown. However, work in my laboratory on the transcription factor Runx2 has revealed a fundamental molecular link between breast and bone-specific gene expression (Inman and Shore, 2003; Inman et al, 2005, Shore, 2005). Evidence is now accumulating that Runx2 controls metastatic cell invasion and contributes to tumour growth and osteolytic disease. Our ongoing research is focussed on identifying Runx2-regulated genes in metastatic cancer cells that contribute to invasion and early colonization phases of the bone microenvironment.

Regulation of Runx2 function

The transcription factor Runx2 is essential for development of the skeleton whereas Oct-1 is a ubiquitous transcription factor involved in the regulation of numerous genes. We have recently identified a novel complex formed between these two important transcription factors (Inman et al, 2005). We are using a “ChIP on chip” approach to identify Runx2/Oct-1 target genes. We have also shown that Oct-1 counteracts auto-inhibition of Runx2 DNA-binding to stimulate the formation of the Runx2/Oct-1 complex. Auto-inhibition of DNA-binding is a potent mechanism to repress the activity of a transcription factor and mechanisms to counteract it are often central to the regulation of transcription factor function. We therefore aim to elucidate the molecular mechanism of Runx2 auto-inhibition and establish the extent to which other Runx2-interacting partners modulate auto-inhibition.