Prostaglandin E2 Inhibits p53 in Human Breast Adipose Stromal Cells: A Novel Mechanism for the Regulation of Aromatase in Obesity and Breast Cancerl

被引:44
作者
Wang, Xuyi [1 ,2 ]
Docanto, Maria M. [1 ]
Sasano, Hironobu [3 ]
Lo, Camden
Simpson, Evan R. [1 ,5 ]
Brown, Kristy A. [1 ,2 ,6 ]
机构
[1] MIMR PHI Inst Med Res, Ctr Canc Res, Metab & Canc Lab, Clayton, Vic 3168, Australia
[2] Monash Univ, Dept Physiol, Clayton, Vic, Australia
[3] Tohoku Univ, Sch Med, Dept Pathol, Sendai, Miyagi 980, Japan
[4] Univ Melbourne, Sir Peter MacCallum Canc Ctr, Dept Oncol, Melbourne, Vic, Australia
[5] Monash Univ, Clayton, Vic, Australia
[6] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic, Australia
基金
英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;
关键词
P450; CYP19; GENE; TUMOR-SUPPRESSOR; CYCLIC-AMP; TRANSCRIPTIONAL REPRESSION; PROXIMAL PROMOTER; MAMMARY-GLAND; EXPRESSION; INFLAMMATION; TISSUE; RECEPTOR;
D O I
10.1158/0008-5472.CAN-14-2164
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Obesity is a risk factor for postmenopausal breast cancer and the majority of these cancers are estrogen dependent. Aromatase converts androgens into estrogens and its increased expression in breast adipose stromal cells (ASC) is a major driver of estrogen receptor-positive breast cancer. In particular, obesity-associated and tumor-derived factors, such as prostaglandin E-2 (PGE(2)), have been shown to drive the expression of aromatase by stimulating the activity of the proximal promoter II (PII). The tumor-suppressor p53 is a key regulator of cell-cycle arrest and apoptosis and is frequently mutated in breast cancer. Mutations in p53 are rare in tumor-associated ASCs. Therefore, it was hypothesized that p53 is regulated by PGE(2) and involved in the PGE(2)-mediated regulation of aromatase. Results demonstrate that PGE(2) causes a significant decrease in p53 transcript and nuclear protein expression, as well as phosphorylation at Ser15 in primary human breast ASCs. Stabilization of p53 with RITA leads to a significant decrease in the PGE(2)-stimulated aromatase mRNA expression and activity, and PII activity. Interaction of p53 with PII was demonstrated and this interaction is decreased in the presence of PGE(2). Moreover, mutation of the identified p53 response element leads to an increase in the basal activity of the promoter. Immunofluorescence on clinical samples demonstrates that p53 is decreased in tumor-associated ASCs compared with ASCs from normal breast tissue, and that there is a positive association between perinuclear (inactive) p53 and aromatase expression in these cells. Furthermore, aromatase expression is increased in breast ASCs from Li-Fraumeni patients (germline TP53 mutations) compared with non-Li-Fraumeni breast tissue. Overall, our results demonstrate that p53 is a negative regulator of aromatase in the breast and its inhibition by PGE(2) provides a novel mechanism for aromatase regulation in obesity and breast cancer. (C)2015 AACR.
引用
收藏
页码:645 / 655
页数:11
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