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Published on: December 11, 2017

Role for HER2/neu and HER3 in fulvestrant-resistant breast cancer

Clodia Osipo1, Kathleen Meeke, Dong Cheng

  • 1Department of Pathology, Oncology Institute, Cardinal Bernadin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.

International Journal of Oncology
|January 5, 2007
PubMed

Insights

Tamoxifen-resistant breast cancer can be stimulated by fulvestrant, not via estrogen receptor alpha (ERalpha) activity. Instead, growth is mediated by the HER2/HER3 pathway, which can be targeted by pertuzumab.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Tamoxifen resistance is a significant challenge in estrogen receptor alpha (ERalpha)-positive breast cancer treatment.
  • Fulvestrant is a second-line therapy, but its paradoxical growth-stimulating effects in tamoxifen-resistant models require mechanistic investigation.
  • Estrogen-responsive gene expression is a key indicator of ERalpha activity in breast cancer.

Purpose of the Study:

  • To investigate the mechanisms underlying fulvestrant-induced growth in tamoxifen-resistant MCF-7 xenografts (MCF-7TAMLT) in the presence of estradiol.
  • To evaluate therapeutic strategies targeting identified growth pathways in vivo.
  • To determine the role of the HER2/HER3 pathway in fulvestrant-mediated tumor growth.

Main Methods:

  • Xenograft models of tamoxifen-sensitive (MCF-7E2) and tamoxifen-resistant (MCF-7TAMLT) breast cancer were established in athymic mice.
  • Gene and protein expression analysis (c-myc, igf-1, cathepsin D, pS2, HER2/neu, HER3, ERK-1/2, GSK3alpha/beta) was performed.
  • In vivo efficacy of pertuzumab, a HER2/HER3 inhibitor, was assessed in fulvestrant-treated MCF-7TAMLT xenografts.

Main Results:

  • Estradiol increased estrogen-responsive gene expression, while tamoxifen and fulvestrant decreased it in both models.
  • Fulvestrant treatment in MCF-7TAMLT tumors led to increased levels of phosphorylated HER2/neu, HER3, ERK-1/2, and GSK3alpha/beta.
  • Pertuzumab significantly inhibited the growth of fulvestrant-treated MCF-7TAMLT xenografts by 37.2% and reduced HER2/HER3 interaction.

Conclusions:

  • Tumor growth in tamoxifen-resistant models treated with tamoxifen or fulvestrant may be independent of ERalpha transcriptional activity.
  • Fulvestrant-induced growth in this model is partially mediated by enhanced signaling through the HER2/HER3 pathway.
  • Targeting the HER2/HER3 pathway with pertuzumab represents a potential therapeutic strategy for fulvestrant-resistant breast cancer.

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