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Updated: Nov 5, 2025

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Steroid Ligands, the Forgotten Triggers of Nuclear Receptor Action; Implications for Acquired Resistance to Endocrine

Rachel Bleach1, Stephen F Madden2, James Hawley3

  • 1Endocrine Oncology Research, Department of Surgery, RCSI University of Medicine and Health Sciences, Dublin, Ireland.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|May 21, 2021
PubMed
Abstract

Insights

Adrenal androgens, acting through the androgen receptor (AR), may drive endocrine-resistant breast cancer. Targeting AR and understanding the steroid microenvironment are crucial for effective breast cancer treatment.

Area of Science:

  • Endocrinology
  • Oncology
  • Molecular Biology

Background:

  • Estrogens are not the only steroid drivers of breast cancer.
  • Adrenal androgenic steroid precursors may promote endocrine-resistant breast cancer via the androgen receptor (AR).

Purpose of the Study:

  • To investigate the role of AR and adrenal androgens in breast cancer endocrine resistance.
  • To evaluate AR expression and androgen levels in breast cancer patients.
  • To analyze AR and estrogen receptor (ER) signaling in response to aromatase inhibitor (AI) therapy.

Main Methods:

  • AR protein expression was assessed in breast cancer tissue microarrays.
  • Serum androstenedione (4AD) levels were measured.
  • Steroid levels (androgens, progesterone, estradiol) were quantified using LC/MS-MS.
  • AR and ER signaling pathway activities were analyzed in AI-treated cohorts.

Main Results:

  • AR protein expression correlated with favorable progression-free survival.
  • Decreasing 4AD levels with age were observed in nonrecurrent breast cancer patients.
  • Altered steroid levels were detected before and after AI therapy.
  • An increased AR:ER signaling ratio was found in patients resistant to AI therapy.
  • 4AD mediated gene changes associated with acquired AI resistance.

Conclusions:

  • The steroid microenvironment and receptor activation are important in breast cancer therapy.
  • Examining AR signaling and steroid levels can inform breast cancer treatment strategies.

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