A role for CBFβ in mammary gland development and breast carcinogenesis

Abstract

Breast cancer is a heterogeneous disease with a high survival rate when localised but a very poor prognosis in the metastatic stage of the disease. Recent whole genome/exon sequencing studies using human breast tumours have identified Cbf, for the first time, as a gene that is significantly mutated in breast cancer, alongside well-documented key players including TP53, GATA3, MAP3KI and PIK3CA. With Cbfβ mutated in ~5% of luminal breast cancers, it is one of the most frequently mutated genes but has not been previously linked to breast cancer. Cbfβ is the binding partner of the osteogenic transcription factor Runx2, for which a novel role as a regulator of mammary gland development and tumourigenesis has recently been shown. All members of the Runx family form heterodimeric complexes with the same co-transcription factor, core binding factor  (Cbf). This complex can either activate or repress transcription of key regulators of growth, survival and differentiation pathways. This thesis describes a novel and exciting role for Cbfb in the regulation of normal mammary gland development, breast cancer progression and distal metastasis both in vitro and in vivo. This indicates a potential new definition for Cbfb as transcriptional master regulator capable of directing breast cancer pathogenesis.