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Steroid ligands, the forgotten triggers of nuclear receptor action; implications for acquired resistance to endocrine therapy

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journal contribution
posted on 10.06.2021, 16:21 by Rachel Bleach, Stephen Madden, James Hawley, Sara Charmsaz, Cigdem Selli, Katherine Sheehan, Leonie Young, Andrew H Sims, Pavel Soucek, Arnold Hill, Marie McIlroy

Purpose: There is strong epidemiological evidence which indicates that estrogens may not be the sole steroid drivers of breast cancer. We hypothesize that abundant adrenal androgenic steroid precursors, acting via the androgen receptor (AR), promote an endocrine resistant breast cancer phenotype.

Experimental design: AR was evaluated in a primary breast cancer tissue-microarray (n=844). Androstenedione (4AD) levels were evaluated in serum samples (n=42) from hormone receptor positive, post-menopausal breast cancer. Levels of androgens, progesterone and estradiol were quantified using LC-MS/MS in serum from age and grade-matched recurrent and non-recurrent patients (n=6) pre- and post-aromatase inhibitor (AI) therapy (>12 months). Androgen and estrogen receptor signaling pathways activities were analyzed in two independent AI treated cohorts.

Results: AR protein expression was associated with favorable progression-free survival in the total population (Wilcoxon, p<0.001). Breast cancer patients pre-therapy showed decreasing levels of 4AD with age only in the non-recurrent group (p<0.05). LC-MS/MS analysis of an AI sensitive and resistant cohort demonstrated the ability to detect altered levels of steroids in serum of patients pre and post AI-therapy. Transcriptional analysis showed an increased ratio of AR: ER signaling pathway activities in patients failing AI therapy (t-test p<0.05), furthermore, 4AD mediated gene changes associated with acquired AI resistance.

Conclusions: This study highlights the importance of examining the therapeutic consequences of the steroid microenvironment and demonstrable receptor activation using indicative gene expression signatures.

Funding

PROJECT TITLE: INVESTIGATION INTO THE ANDROGEN RECEPTOR AND THE CLINICAL RELEVANCE OF CIRCULATING ANDROGENS | Funder: Beaumont Hospital Cancer Research Trust | Grant ID: N/A

Ministry of Health of the Czech Republic (project no. 17-28470A)

Breast Cancer Ireland (CTI 09/07)

History

Comments

The original article is available at https://clincancerres.aacrjournals.org

Published Citation

Bleach R, Madden SF, Hawley J, Charmsaz S, Selli C, Sheehan KM, Young LS, Sims AH, Soucek P, Hill AD, McIlroy M. Steroid ligands, the forgotten triggers of nuclear receptor action; implications for acquired resistance to endocrine therapy. Clin Cancer Res. 2021:clincanres.4135.2020.

Publication Date

20 May 2021

PubMed ID

34016642

Department/Unit

  • Beaumont Hospital
  • Data Science Centre
  • Surgery

Research Area

  • Cancer
  • Endocrinology

Publisher

American Association for Cancer Research (AACR)

Version

  • Published Version (Version of Record)