p53, a Target of Estrogen Receptor (ER) α, Modulates DNA Damage-induced Growth Suppression in ER-positive Breast Cancer Cells

In response to genotoxic stress, the p53 tumor suppressor induces target genes for cell cycle arrest, apoptosis, and DNA repair. Although p53 is the most commonly mutated gene in all human cancers, it is only mutated in about 20% of breast cancers. 70% of all breast cancer cases are estrogen receptor (ER)positive and express ER alpha. ER-positive breast cancer generally indicates good patient prognosis and treatment responsiveness with antiestrogens, such as tamoxifen. However, ER-positive breast cancer patients can experience loss or a reduction in ER alpha, which is associated with aggressive tumor growth, increased invasiveness, poor prognosis, and loss of p53 function. Consistent with this, we found that p53 is a target gene of ER alpha. Specifically, we found that knockdown of ER alpha decreases expression of p53 and its downstream targets, MDM2 and p21. In addition, we found that ER alpha activates p53 transcription via binding to estrogen response element half-sites within the p53 promoter. Moreover, we found that loss of ER alpha desensitizes, whereas ectopic expression of ER alpha sensitizes, breast cancer cells to DNA damage-induced growth suppression in a p53-dependent manner. Altogether, this study provides an insight into a feedback loop between ER alpha and p53 and a biological role of p53 in the DNA damage response in ER-positive breast cancers.