Estrogen levels act as a rheostat on p53 levels and modulate p53-dependent responses in breast cancer cell lines

Abstract

A large proportion of breast cancers expresses the estrogen receptor alpha (ERα) and are dependent on estrogens for their proliferation and survival. The tumor suppressor TP53 encodes the p53 protein, an important mediator of the anti-proliferative and apoptotic effects of several treatments used for breast cancer. A significant proportions of breast tumors (20-30%) carry mutations in TP53 gene and these mutations are associated with poor survival and poor response to several types of chemotherapeutic treatments. While there is mounting evidence for functional interactions between p53 and ERα pathways in breast and other tissues, the impact of these interactions on response to chemotherapy and anti-hormone treatments remain largely unknown. Here, using estrogen-dependent breast cancer cell lines with different p53 status, we show that estrogens, through ERα, influence p53 protein levels and activities. Estrogen deprivation reduced, while estradiol increased p53 levels, in a time and dose-dependent manner. Both wild-type and endogenously expressed mutant p53 proteins were affected. This reduction in p53 protein levels resulted in reduced p53-dependent responses induced by DNA damage in p53 wild-type cells, lowering the capacity of doxorubicine to induce apoptosis. The p53 response appeared to be quantitatively but not qualitatively affected. These results suggest that ERα activity is required for a strong p53 response in estrogen-dependent breast cancer cells. These results are in line with previous observations that we made in a clinical series, where a larger effect of TP53 mutation status was found for patient survival in cases with progesterone receptor positive status, a marker of a functional ERα pathway. It would thus be important to further characterize the influence of ERα pathway on the predictive value of TP53 mutation status in specifically designed clinical trials, as it may open perspectives for improving breast cancer treatment.