Role of NAMPT/NMNATs-SIRTs-tumor suppressor proteins nexus in breast cancer

The cells in our body use proteins called tumour suppressors to suppress the development of cancerous cells. One of the most well-known tumour suppressors is p53. Not surprisingly, many anti-cancer therapies aim to "boost" p53 functions in cancer, including breast cancer. Unfortunately, p53 itself is often lost or mutated in most cancers, making such efforts difficult, if not futile. Recent focus has turned to another protein, a "cousin" of p53 called p73 that shares similar tumour suppressing functions as p53 but is rarely lost or mutated. Thus, the activation of p73 represents a valid strategy to treat cancers by promoting its tumor suppressing functions. Acetylation is a major mechanism of protein activation, and this is counteracted by deacetylation. The Sirtuins (SIRTs) are a group of deacetylase enzymes that play important roles in the latter process. To remove the acetyl groups, SIRTs require an important cofactor called NAD+. The synthesis of NAD+ is in turn catalyzed by two enzymes: NAMPT (nicotinamide phosphoribosyltransferase) and NMNATs (nicotinamide mononucleotide adenylyltransferase isoforms 1, 2 and 3). Hence, I hypothesize that p73 is likely regulated by NAMPT/NMNATs via SIRTs. Using breast cancer cells, I found that a link (an inverse relationship) exists between NAMPT and p73. In these cells, NAMPT levels are high, which in turn reduces p73 levels. Analysis of data from 176 breast cancer patients also shows that high NAMPT/NMNATs and low p73 levels (but not p53 levels) correlate with higher tumour grades and poorer patient survival. The proposed research will focus on this NAMPT/NMNATs-SIRTs-p73 connection in breast cancer and its impact on diagnosis, prognosis, and treatment of breast cancer. We believe that the findings from this exciting project will shed light on a new set of breast cancer biomarkers, and will promote the development of novel anti-cancer treatment interventions against breast cancer.