P53 genotype as a determinant of ER expression and tamoxifen response in the MMTV-Wnt-1 model of mammary carcinogenesis.
P53 genotype as a determinant of ER expression and tamoxifen response in the MMTV-Wnt-1 model of mammary carcinogenesis.
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DOI：
10.1007/s10549-010-1308-y
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发表时间：
2011-11
影响因子：
3.8
通讯作者：
Hursting, Stephen D.
中科院分区：
文献类型：
--
作者：
Fuchs-Young, Robin;Shirley, Stephanie H.;Lambertz, Isabel;Colby, Jennifer K. L.;Tian, Jie;Johnston, Dennis;Gimenez-Conti, Irma B.;Donehower, Lawrence A.;Conti, Claudio J.;Hursting, Stephen D.
临床研究表明，表达雌激素受体-α（ER）的肿瘤往往具有更好的预后，对抗雌激素治疗有反应，并具有野生型p53。相反，p53失活突变的肿瘤往往有更差的结果，ER阴性，对抗激素治疗无反应。我们实验室以前的研究表明，p53通过结合ER启动子并与CARM 1，CBP，c-Jun，RNA聚合酶II和Sp1形成复合物来转录调节ER表达。在这项研究中，MMTV-Wnt-1转基因小鼠模型被用来证明，ER的表达和功能的p53调节不仅是一个在体外的现象，但它也是在体内乳腺肿瘤发生的操作。在携带Wnt-1转基因的p53野生型（WT）或p53杂合型（HT）动物中产生的乳腺肿瘤中测定ER的表达和对他莫昔芬的应答能力。在p53 WT小鼠中，ER阳性肿瘤的发展被他莫昔芬治疗延迟，而在p53 HT小鼠中产生的肿瘤具有显著降低的ER水平，并且不受他莫昔芬的影响。在p53 HT小鼠中也发现了P53无效肿瘤，并且这些肿瘤是ER阴性的。在用WT p53转染或用多柔比星处理后，ER表达在小鼠乳腺肿瘤细胞系中上调。这些数据表明，p53在体内调节ER表达，并影响对他莫昔芬的反应。结果也提供了一个解释，这些预后蛋白在人类乳腺肿瘤之间的一致性关系。
Clinical studies show that estrogen receptor-α (ER) expressing tumors tend to have better prognosis, respond to antiestrogen therapy and have wild-type p53. Conversely, tumors with inactivating mutations in p53 tend to have worse outcomes and to be ER-negative and unresponsive to antihormone treatment. Previous studies from our laboratory have shown that p53 regulates ER expression transcriptionally, by binding the ER promoter and forming a complex with CARM1, CBP, c-Jun, RNA polymerase II and Sp1. In this study, the MMTV-Wnt-1 transgenic mouse model was used to demonstrate that p53 regulation of ER expression and function is not solely an in vitro phenomenon, but it is also operational in mammary tumorigenesis in vivo. The expression of ER and the ability to respond to tamoxifen were determined in mammary tumors arising in p53 wild type (WT) or p53 heterozygous (HT) animals carrying the Wnt-1 transgene. In p53 WT mice, development of ER-positive tumors was delayed by tamoxifen treatment, while tumors arising in p53 HT mice had significantly reduced levels of ER and were not affected by tamoxifen. P53 null tumors were also found in the p53 HT mice and these tumors were ER-negative. ER expression was upregulated in mouse mammary tumor cell lines following transfection with WT p53 or treatment with doxorubicin. These data demonstrate that p53 regulates ER expression in vivo, and affects response to tamoxifen. Results also provide an explanation for the concordant relationship between these prognostic proteins in human breast tumors.
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影响因子：
4
作者：
Angeloni, SV;Martin, MB;Saceda, M
通讯作者：
Saceda, M
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A
影响因子：
3.1
作者：
Alsner, Jan;Jensen, Vibeke;Overgaard, Jens
通讯作者：
Overgaard, Jens
影响因子：
120.7
作者：
Cummings, SR;Eckert, S;Jordan, VC
通讯作者：
Jordan, VC
DOI：
10.1073/pnas.1009575107
发表时间：
2010-08-24
影响因子：
11.1
作者：
Konduri, Santhi D.;Medisetty, Rajesh;Das, Gokul M.
通讯作者：
Das, Gokul M.