Divide and conquer: the genetic basis of molecular subclassification of breast cancer

Abstract

Since the luminal B tumours are associated with poor recurrence-free and disease-specific survivals in all adjuvant systemic treatment categories including hormone therapy, the identification of specific signalling pathways driving luminal B biology is paramount to improve treatment. Sircoulomb et al. and Holland et al. have independently identified the ZNF703 gene, located in chromosomal region 8p12, as preferentially amplified in luminal B tumours.

Figure 1. ZNF703 function in luminal B breast cancer

Transcription of the amplified ZNF703 gene is activated by E2-ESR1 signalling. ZNF703 forms a nuclear repressor complex together with DCAF7, HSP60 and PHB2 (Prohibitin 2). ZNF703 was found to co-localize with HDAC1 on promoters with H3Kme1 or H3K4me3 labels suggesting mediation of active repressing of genes such as PAX2 and TGFBP2. The enhanced levels of ZNF703 lead to a variety of downstream effects like downregulation of important ER transcriptional targets and up-regulation of E2F1 with following increase in RB phosphorylation and decrease of P27kip1with subsequent cell cycle progression into proliferation depending on the subtype of mammary cell.