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Mechanisms of hormonal therapy resistance in breast cancer

Shin-ichi Hayashi1, Mariko Kimura

  • 1Department of Molecular and Functional Dynamics, and Center for Regulatory Epigenomics and Diseases, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan, shin@med.tohoku.ac.jp.

International Journal of Clinical Oncology
|February 6, 2015
PubMed

Insights

Hormone therapy resistance in estrogen receptor-positive breast cancer involves diverse mechanisms. Understanding these alternative signaling pathways is crucial for developing targeted therapies and improving patient outcomes.

Area of Science:

  • Oncology
  • Endocrinology
  • Molecular Biology

Background:

  • Estrogen receptor (ER)-positive breast cancer is often treated with hormone therapy.
  • Approximately one-third of patients treated with hormone therapy experience relapse.
  • Mechanisms of hormone therapy resistance, particularly aromatase inhibitor (AI) resistance, are not fully understood.

Purpose of the Study:

  • To investigate the mechanisms of AI resistance in ER-positive breast cancer.
  • To identify alternative intracellular ER signaling pathways involved in resistance.
  • To explore the potential for further subclassification of ER-positive breast cancer for improved therapeutic management.

Main Methods:

  • Analysis of AI-refractory breast cancer specimens using the adenovirus estrogen receptor element-green fluorescent protein (ERE-GFP) assay.
  • Establishment and characterization of six distinct AI-resistant ER-positive cell line models.
  • Monitoring of ER transcription activity and assessment of sensitivity to anti-estrogens, fulvestrant, and mTOR inhibitors.

Main Results:

  • AI-refractory specimens exhibited diverse ER activity and varied sensitivity to anti-estrogens, suggesting multiple resistance mechanisms.
  • Established resistant cell lines revealed involvement of multiple and alternative ER activating pathways, including phosphorylation-dependent and androgen metabolite-dependent mechanisms.
  • Individual resistant cell lines showed differential responses to fulvestrant and mammalian target of rapamycin (mTOR) inhibitors.

Conclusions:

  • Multiple and alternative ER activating pathways contribute to AI resistance in ER-positive breast cancer.
  • The heterogeneity of resistance mechanisms underscores the need for further subclassification of ER-positive breast cancer.
  • Accurate subclassification is essential for guiding therapeutic decisions, including hormonal therapy and novel molecular targeted therapies.

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