Progress in the research of p53 tumour suppressor activity controlled by Numb in triple-negative breast cancer.

ABSTRACT

Numb is known as a cell fate determinant as it identifies the direction of cell differentiation via asymmetrical partitioning during mitosis. It is considered as a tumour suppressor, and a frequent loss of Numb expression in breast cancer is noted. Numb forms a tri-complex with p53 and E3 ubiquitin ligase HDM2 (also known as MDM2), thereby preventing the ubiquitination and degradation of p53. In this study, we examined Numb expression in 125 patients with triple-negative breast cancer (TNBC). The results showed that 61 (48.8%) patients presented with a deficient or decreased Numb expression. The percentage of Ki67 > 14% in the retained Numb group was significantly lower than that in the decreased and deficient Numb groups (86.00% vs. 98.40%, P = .0171). This study aimed to detect the expression and migration of Numb, HDM2 and p53 in the membrane, cytoplasmic and nuclear fractions of normal mammary epithelial cell line MCF-10A and basal-like TNBC cell line MDA-MB-231. We obtained the cell fractions to identify changes in these three protein levels after the re-expression of NUMB in the MDA-MB-231 cells and the knocking down of NUMB in the MCF-10A cells. Results showed that Numb regulates p53 levels in the nucleus where the protein levels of Numb are positively correlated with p53 levels, regardless if it is re-expressed in the MDA-MB-231 cells or knocked down in the MCF-10A cells. Moreover, HDM2 was remarkably decreased only in the membrane fraction of NUMB knock-down cells; however, its mRNA levels were increased significantly. Our results reveal a previously unknown molecular mechanism that Numb can migrate into the nucleus and interact with HDM2 and p53.