Breast cancer is the most common malignancy in women, with the second highest cancer-related death rates. Estrogen receptor α (ERα) and p53 are essential for normal breast growth and are critical indicators in breast cancer prognostication. p53 can inhibit estrogen responses by modulating the expression and activity of ERα, and loss of this control is associated with poor outcome in breast cancer. Our previous studies have indicated that △40p53 is the most highly expressed p53 isoform in breast cancer (Carcinogenesis 2014;35(3):586–96), but the functional relevance is unknown. Here, we investigated the potential of △40p53 to modulate the ERα signalling pathway.
Using qPCR, we have shown that △40p53 was correlated (p<0.05) with expression of ERα, its target genes PR and pS2; and the proliferation marker Ki67 in 113 ERα-positive tumours. siRNA-mediated knockdown of △40p53 in MCF-7 cells reduced proliferation. In addition, siRNA knockdown of △40p53 reduced estradiol-induced expression of ERα, PR and pS2, suggesting △40p53 can enhance ERα-mediated signalling. These results were complemented by analysis of △40p53-overexpressing cells. To determine other potential pathways regulated by △40p53, whole genome microarrays were performed on a subset of tumours (ERα-positive n=38, ERα-negative n=26). Interestingly, there were many significant differences (p<0.05, FC<1.5, FDR 5%) in gene expression profiles of breast tumours with high △40p53 compared to low △40p53 in ERα-positive cases, while there were no differences in ERα-negative cases, further implicating △40p53 in modulation of estrogen-regulated pathways. Taken together, these results suggest that △40p53 can enhance ERα signalling and this may result in unopposed estrogen action leading to increased breast cancer proliferation.