Related Experiment Video
Updated: Nov 21, 2025
Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
Published on: February 21, 2014
The androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancer
Theresa E Hickey1, Luke A Selth1,2,3, Kee Ming Chia4
1Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
Abstract:
The role of the androgen receptor (AR) in estrogen receptor (ER)-α-positive breast cancer is controversial, constraining implementation of AR-directed therapies. Using a diverse, clinically relevant panel of cell-line and patient-derived models, we demonstrate that AR activation, not suppression, exerts potent antitumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses. Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators (p300, SRC-3), resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER-positive breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER-positive breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.
Insights
Androgen receptor (AR) activation, not suppression, shows potent antitumor effects in estrogen receptor (ER)-positive breast cancer. AR agonists offer a promising therapeutic strategy, revealing AR
Area of Science:
- Oncology
- Endocrinology
- Molecular Biology
Background:
- The role of the androgen receptor (AR) in estrogen receptor (ER)-α-positive breast cancer remains controversial, limiting AR-targeted therapies.
- Current understanding of AR's function in ER-positive breast cancer is insufficient for clinical application.
Purpose of the Study:
- To investigate the precise role of AR activation versus suppression in ER-positive breast cancer.
- To evaluate AR agonism as a therapeutic strategy, particularly in treatment-resistant contexts.
Main Methods:
- Utilized a diverse panel of cell-line and patient-derived models of ER-positive breast cancer.
- Assessed the effects of AR activation (agonism) and suppression (antagonism) on tumor growth.
- Analyzed genomic distribution of ER, co-activators, and gene expression changes upon AR activation.
- Correlated AR activity gene signatures with clinical outcomes in patient cohorts.
Main Results:
- AR activation demonstrated significant antitumor activity across various ER-positive breast cancer models.
- AR agonists showed efficacy even in models resistant to standard ER and CDK4/6 inhibitors.
- Combination therapy with AR agonists and standard agents improved therapeutic responses.
- AR activation modulated ER and co-activator binding, repressing cell cycle genes and upregulating tumor suppressor genes.
- A gene signature of AR activity positively predicted patient survival in clinical ER-positive breast cancer cohorts.
Conclusions:
- AR functions as a tumor suppressor in ER-positive breast cancer.
- AR agonism represents an optimal and rational therapeutic strategy for ER-positive breast cancer.
More Related Videos
08:48An In Vitro Dormancy Model of Estrogen-sensitive Breast Cancer in the Bone Marrow: A Tool for Molecular Mechanism Studies and Hypothesis Generation
Published on: June 30, 2015
10:36Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Related Concept Videos
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
02:38Mitogens and the Cell Cycle
02:23Abnormal Proliferation
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...