Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 30117-30127 |
| Number of pages | 11 |
| Journal | Journal of Biological Chemistry |
| Volume | 287 |
| Issue number | 36 |
| DOIs | |
| State | Published - Aug 31 2012 |
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ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
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p53, a target of estrogen receptor (ER) α, modulates DNA damage-induced growth suppression in ER-positive breast cancer cells. / Berger, Crystal E.; Qian, Yingjuan; Liu, Gang; Chen, Hongwu; Chen, Xinbin.
In: Journal of Biological Chemistry, Vol. 287, No. 36, 31.08.2012, p. 30117-30127.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - p53, a target of estrogen receptor (ER) α, modulates DNA damage-induced growth suppression in ER-positive breast cancer cells
AU - Berger, Crystal E.
AU - Qian, Yingjuan
AU - Liu, Gang
AU - Chen, Hongwu
AU - Chen, Xinbin
PY - 2012/8/31
Y1 - 2012/8/31
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84865767406&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84865767406&partnerID=8YFLogxK
U2 - 10.1074/jbc.M112.367326
DO - 10.1074/jbc.M112.367326
M3 - Article
C2 - 22787161
AN - SCOPUS:84865767406
VL - 287
SP - 30117
EP - 30127
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 36
ER -