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Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells
Published on: May 1, 2020
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HE4 expression is associated with hormonal elements and mediated by importin-dependent nuclear translocation
Elizabeth Lokich1, Rakesh K Singh2, Alex Han1
11] 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].
Scientific Reports
|July 1, 2014
Summary
Human epididymis protein 4 (HE4) drives antiestrogen resistance in ovarian cancer by interacting with estrogen receptor-alpha. Importin inhibitors like ivermectin may overcome this resistance, sensitizing cancer cells to hormonal therapies.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Antiestrogens like tamoxifen and fulvestrant are explored for platinum-resistant ovarian cancer.
- Human epididymis protein 4 (HE4) is overexpressed in ovarian cancer and linked to platinum resistance.
- The role of HE4 in hormonal therapy response in ovarian cancer remains unclear.
Purpose of the Study:
- To investigate the role of HE4 in modulating ovarian cancer response to hormonal therapy.
- To characterize the interaction between HE4, estrogen receptor-alpha (ER-α), and nuclear transport.
- To explore importin inhibition as a strategy to overcome HE4-mediated antiestrogen resistance.
Main Methods:
- Investigated the effect of 17β-estradiol, tamoxifen, and fulvestrant on HE4 localization.
- Assessed the interaction between HE4 and ER-α using in vitro and human ovarian cancer samples.
- Utilized importin inhibitors, specifically ivermectin, to block HE4 nuclear transport.
Main Results:
- 17β-estradiol, tamoxifen, and fulvestrant induced nuclear and nucleolar translocation of HE4.
- HE4 overexpression conferred resistance to antiestrogens and led to ER-α downregulation.
- HE4 interacts with ER-α, and importin-4 mediates HE4 nuclear transport.
- Ivermectin treatment blocked HE4 nuclear accumulation and sensitized HE4-overexpressing cells to antiestrogens.
Conclusions:
- HE4 plays a critical role in mediating resistance to antiestrogen therapy in ovarian cancer.
- Targeting HE4 nuclear import via importin inhibitors represents a potential therapeutic strategy.
- Combined therapy with importin inhibitors and antiestrogens may overcome treatment resistance in ovarian cancer.
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