Steroid Ligands, the Forgotten Triggers of Nuclear Receptor Action; Implications for Acquired Resistance to Endocrine Therapy
It is now appreciated that changes in tumor gene and protein expression are influenced by age-dependent host endocrine factors as well as therapy-induced alterations in the steroid hormone milieu. By merging tumor androgen receptor (AR) protein expression and circulating steroid levels, we profiled patients with acquired resistance to aromatase inhibitor (AI) therapy. AR protein expression alone significantly associates with favorable progression-free survival in the total population (n = 844). However, steroid analysis of estrogen receptor (ER)-positive AI-sensitive and AI-resistant patient cohorts showed an ability to detect dynamic changes in circulating steroid levels in patients on AI treatment. Furthermore, acquired AI resistance associated with an increased ratio of AR:ER signaling pathway activities and androstenedione-associated gene changes. This study highlights the importance of examining the therapeutic consequences of the steroid microenvironment and demonstrable receptor activation using indicative gene expression signatures.