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 ERα. 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 ERα, 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 ERα. Specifically, we found that knockdown of ERα decreases expression of p53 and its downstream targets, MDM2 and p21. In addition, we found that ERα activates p53 transcription via binding to estrogen response element half-sites within the p53 promoter. Moreover, we found that loss of ERα desensitizes, whereas ectopic expression of ERα 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 ERα and p53 and a biological role of p53 in the DNA damage response in ER-positive breast cancers.
Comparative Oncology Laboratory, University of California, Davis, CA 95616, USA.
Crystal E
CE
Berger
Yingjuan
Y
Qian
Gang
G
Liu
Hongwu
H
Chen
Xinbin
X
Chen
D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
D004273:DNA, Neoplasm; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2