Defective Signalling of the BRCA1 Neighbouring gene, NBR2, leads to ER-? Negative tumours in breast cancer xenograft mouse models

Abstract

Majority of breast and ovarian cancer treatment modalities are based on endocrine therapies like antiestrogens which are dependent on the hormone receptor status of tumours. Although BRCA1 is a major regulator of Estrogen Receptor (ER-α), BRCA1 mutations are largely limited to hereditary cases. Here, we show the role of NBR2 (neighbour of BRCA1) in regulating ER-α. We demonstrate a positive correlation between NBR2 & ESR1 in TCGA datasets. Further, the study revealed that shRNA-mediated knockdown of NBR2 led to the downregulation of ER-α in breast cancer cells, MCF7. Finally, the downregulation of ER-α in NBR2 knockdown xenograft tumours (in female NSG mice), which showed higher invasive properties than wild type tumours was demonstrated. Thus, we concluded that in ER-α negative tumours with NBR2 deficiency, biguanides such as metformin and phenformin, which are reported to have a better efficacy under NBR2 deficient conditions, could serve as more suitable alternatives to antiestrogens.

Keywords

• breast cancer
• er-α
• nbr2