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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
PubMed

Insights

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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