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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer

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Breast Cancer Resistance to Antiestrogens Is Enhanced by Increased ER Degradation and ERBB2 Expression

Tomohiro Shibata1, Kosuke Watari1, Hiroto Izumi2

  • 1Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

Cancer Research
|November 24, 2016
PubMed

Insights

The transcription factor YBX1 drives resistance to endocrine therapies in estrogen receptor-positive breast cancer by promoting ER degradation and ERBB2 activation. This YBX1 mechanism bypasses antiestrogen treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Endocrine therapies are crucial for estrogen receptor (ER)-positive breast cancer treatment.
  • Drug resistance, particularly to antiestrogens like fulvestrant, poses a significant clinical challenge.
  • Understanding resistance mechanisms is vital for improving patient outcomes.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying antiestrogen resistance in ER-positive breast cancer.
  • To investigate the role of the transcription factor YBX1 in endocrine therapy resistance.

Main Methods:

  • Utilized breast cancer cell lines with acquired resistance to fulvestrant.
  • Assessed the impact of YBX1 expression and phosphorylation on ER and ERBB2 levels.
  • Investigated YBX1 binding to ER and the ERBB2 promoter using molecular assays.
  • Evaluated the in vitro and in vivo effects of YBX1 on tamoxifen and fulvestrant resistance.

Main Results:

  • YBX1 overexpression conferred resistance to tamoxifen and fulvestrant.
  • YBX1 overexpression correlated with decreased ER and increased ERBB2 levels.
  • YBX1 directly binds ER, accelerating its proteasomal degradation.
  • YBX1 induces ERBB2 transcriptional activation and enhances ERBB2 expression upon tamoxifen treatment.

Conclusions:

  • YBX1 plays a causative role in antiestrogen resistance in ER-positive breast cancer.
  • YBX1 promotes antiestrogen bypass by degrading ER and upregulating ERBB2.
  • Targeting YBX1 may represent a therapeutic strategy to overcome endocrine resistance.

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