The CBFß transcription factor has recently been identified by three separate whole genome/exon sequencing studies as a gene with recurrent mutations across an array of human breast cancer patients.
CBFß is a co-activator, which forms heterodimeric complexes with all members of the Runx family, ensuring high affinity DNA binding. RUNX2 is most well known as a master regulator of bone development, however our lab has recently shown a novel role for RUNX2 in breast development and carcinogenesis.
The overall aim of this project is to determine the role of the Runx and CBFß transcription factors in mammary gland cell fate specification and the mechanisms by which they control normal mammary gland development and influence breast carcinogenesis and metastasis.
Our work focuses on altering levels of CBFß expression to investigate the effects of perturbing RUNX2 levels. This approach compensates for the potential redundancy that exists between members of the Runx family. We have examined these effects both in vitro and in vivo and have found thus far that CBFß has a critical role in both the development of the mammary gland and also in the ability of breast cancer cells to control phenotypes consistent with metastasis, such as proliferation and migration. Furthermore, we have shown that knocking out CBFß in the mouse mammary gland delays tumour onset and increases overall survival in breast carcinogenesis whilst also reducing the incidence and severity of distal metastases.
We report that RUNX2 and CBFß expression are differentially regulated throughout mammary gland development and demonstrate an exciting and novel role for CBFß in mammary gland development, breast carcinogenesis and metastasis in vitro and in vivo. We are currently investigating the underlying mechanisms by which CBFß is able to control mammary cell fate and influence breast cancer progression.