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Glucose-regulated protein 78 controls cross-talk between apoptosis and autophagy to determine antiestrogen

Katherine L Cook1, Ayesha N Shajahan, Anni Wärri

  • 1Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia 20057, USA.

Cancer Research
|July 4, 2012
PubMed

Insights

Glucose-regulated protein 78 (GRP78) overexpression drives endocrine therapy resistance in estrogen receptor-positive (ER+) breast cancer by inhibiting apoptosis and promoting autophagy. Reducing GRP78 restores sensitivity to antiestrogen treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Estrogen receptor-positive (ER+) breast cancer, comprising over 70% of cases, often develops resistance to endocrine therapies.
  • The molecular mechanisms underlying this treatment resistance are not fully understood.
  • Glucose-regulated protein 78 (GRP78) is investigated for its potential role in mediating this resistance.

Purpose of the Study:

  • To investigate the role of glucose-regulated protein 78 (GRP78) in acquired antiestrogen resistance in ER+ breast cancer.
  • To elucidate the molecular mechanisms by which GRP78 mediates endocrine resistance.
  • To explore therapeutic strategies targeting GRP78 to overcome treatment resistance.

Main Methods:

  • Analysis of GRP78 expression in human breast tumors and cell lines.
  • Gene knockdown and overexpression experiments to assess GRP78's effect on antiestrogen sensitivity.
  • Investigation of cellular signaling pathways, including apoptosis and autophagy, in response to GRP78 modulation.
  • Pharmacological inhibition of autophagy and caspase pathways.

Main Results:

  • GRP78 expression was increased in ER+ antiestrogen-resistant cells and tumors with acquired resistance, but not in de novo resistance.
  • Knockdown of GRP78 restored antiestrogen sensitivity, while its overexpression induced resistance.
  • GRP78 integrated signaling pathways to inhibit apoptosis and promote prosurvival autophagy via TSC2/AMPK-mediated mTOR inhibition.
  • Inhibition of autophagy or combined knockdown of GRP78 and beclin-1 synergistically restored sensitivity.

Conclusions:

  • GRP78 plays a critical role in mediating acquired endocrine resistance in ER+ breast cancer.
  • GRP78 influences cell fate by integrating pathways like the unfolded protein response, apoptosis, and autophagy.
  • Targeting GRP78 and/or autophagy presents a potential strategy to overcome antiestrogen resistance.

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