HE4 expression is associated with hormonal elements and mediated by importin-dependent nuclear translocation

被引：27
|
作者：
Lokich, Elizabeth [1 ]
Singh, Rakesh K. [1 ]
Han, Alex [1 ]
Romano, Nicole [1 ]
Yano, Naohiro [1 ]
Kim, Kyukwang [1 ]
Moore, Richard G. [1 ]
机构：
[1] Brown Univ, Women & Infants Hosp, Alpert Med Sch, Dept Obstet & Gynecol,Program Womens Oncol, Providence, RI 02905 USA
来源：
SCIENTIFIC REPORTS | 2014年 / 4卷
关键词：
ESTROGEN-RECEPTOR-ALPHA; ADVANCED BREAST-CANCER; OVARIAN-CANCER; DNA METHYLATION; TREATMENT OPTION; TAMOXIFEN; FULVESTRANT; THERAPY; APOPTOSIS; GENE;
D O I：
10.1038/srep05500
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
Antiestrogens including tamoxifen and fulvestrant have been evaluated as chemotherapeutics for ovarian cancer, particularly in cases of platinum resistant disease. Human epididymis protein 4 (HE4) is highly overexpressed in women with ovarian cancer and overexpression of HE4 has been found to correlate with platinum resistance. However, the role of HE4 in modulating responses to hormones and hormonal therapy has not been characterized in ovarian cancer. Here we demonstrate that 17 beta-estradiol, tamoxifen, and fulvestrant induce nuclear and nucleolar translocation of HE4 and that HE4 overexpression induces resistance to antiestrogens. HE4 was found to interact with estrogen receptor-alpha (ER-alpha), and HE4 overexpression resulted in ER-alpha downregulation in vitro and in human ovarian cancers. We identified a novel role for importin-4 in governing the nuclear transport of HE4. Treatment with ivermectin, an importin inhibitor, blocked HE4/importin-4 nuclear accumulation and sensitized HE4-overexpressing ovarian cancer cells to fulvestrant and tamoxifen.
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页数：9
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