The role of the NDRG1 in the pathogenesis and treatment of breast cancer

Breast cancer (BC) is the leading cause of cancer death in women. This disease is heterogeneous, with clinical subtypes being estrogen receptor-α (ER-α) positive, having human epidermal growth factor receptor 2 (HER2) overexpression, or being triple-negative for ER-α, progesterone receptor, and HER2 (TNBC). The ER-α positive and HER2 overexpressing tumors can be treated with agents targeting these proteins, including tamoxifen and pertuzumab, respectively. Despite these treatments, resistance and metastasis are problematic, while TNBC is challenging to treat due to the lack of suitable targets. Many studies examining BC and other tumors indicate a role for N-myc downstream-regulated gene-1 (NDRG1) as a metastasis suppressor. The ability of NDRG1 to inhibit metastasis is due, in part, to the inhibition of the initial step in metastasis, namely the epithelial-to-mesenchymal transition. Paradoxically, there are also reports of NDRG1 playing a pro-oncogenic role in BC pathogenesis. The oncogenic effects of NDRG1 in BC have been reported to relate to lipid metabolism or the mTOR signaling pathway. The molecular mechanism(s) of how NDRG1 regulates the activity of multiple signaling pathways remains unclear. Therapeutic strategies that up-regulate NDRG1 have been developed and include agents of the di-2-pyridylketone thiosemicarbazone class. These compounds target oncogenic drivers in BC cells, suppressing the expression of multiple key hormone receptors including ER-α, progesterone receptor, androgen receptor, and prolactin receptor, and can also overcome tamoxifen resistance. Considering the varying role of NDRG1 in BC pathogenesis, further studies are required to examine what subset of BC patients would benefit from pharmacopeia that up-regulate NDRG1.