title: HE4 expression is associated with hormonal elements and mediated by importin-dependent nuclear translocation.
abstract: 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 17β-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-α (ER-α), and HE4 overexpression resulted in ER-α 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.
authors: 1] Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Alpert Medical School at Brown University, Providence, RI, 02905, USA [2].
authors: Elizabeth
authors: E
authors: Lokich
authors: Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Alpert Medical School at Brown University, Providence, RI, 02905, USA.
authors: Rakesh K
authors: RK
authors: Singh
authors: 1] Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Alpert Medical School at Brown University, Providence, RI, 02905, USA [2].
authors: Alex
authors: A
authors: Han
authors: Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Alpert Medical School at Brown University, Providence, RI, 02905, USA.
authors: Nicole
authors: N
authors: Romano
authors: Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Alpert Medical School at Brown University, Providence, RI, 02905, USA.
authors: Naohiro
authors: N
authors: Yano
authors: Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Alpert Medical School at Brown University, Providence, RI, 02905, USA.
authors: Kyukwang
authors: K
authors: Kim
authors: Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Alpert Medical School at Brown University, Providence, RI, 02905, USA.
authors: Richard G
authors: RG
authors: Moore
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D028884:Karyopherins / Q000378:metabolism*; D018613:Microscopy, Confocal; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000081102:WAP Four-Disulfide Core Domain Protein 2
chemical_list: D018931:Antineoplastic Agents, Hormonal; D028884:Karyopherins; D011506:Proteins; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol