Constitutive androgen receptor activity sustains DNA replication programs in triple-negative breast cancer.
- 1Hinova Pharmaceuticals Inc, Chengdu, China.
- 2Hinova Pharmaceuticals Inc, Chengdu, China. [email protected].
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. Despite AR expression in nearly half of TNBCs, androgen receptor signaling inhibitors (ARSIs) have shown minimal clinical benefit. In this study, we utilized HP518, a potent PROTAC that selectively degrades AR, to interrogate the role of AR in TNBC. We uncover a non-canonical, androgen-independent function of AR in AR-positive TNBC cells: AR cooperates with transcriptional regulators FoxA1 and GATA3 to promote expression of DNA replication genes critical for tumor proliferation. Genetic and pharmacological degradation of AR suppresses tumor cell growth, downregulates key DNA replication genes, and disrupts AR-associated transcriptional complexes. In AR-positive TNBC patient-derived xenografts (PDX), HP518 robustly inhibits tumor growth and synergizes with PI3Kα inhibition and chemotherapy. Our findings identify a previously unappreciated mechanism of AR action in TNBC and support AR degradation-not antagonism as a rational therapeutic strategy.
Related
- Androgen Receptor SUMO site mutations ameliorate toxicity in Drosophila models of SBMA
- PGC-1α Links Estrogen Receptor Signaling to Japanese Encephalitis Virus Replication in Neuronal cell
- Concurrent TMS-EEG to characterise interhemispheric signal propagation over the motor and prefrontal regions: An independent replication of GABAB receptor mechanisms
- Epigenetic regulation of DPP4 receptor expression by NONO enables replication of MERS-CoV
- Pediatric and adult primary human airway epithelia exhibit similar rhinovirus C replication, innate responses, and expression of protein receptor
BibTeX
@article{li2026constitutive,
title = {{Constitutive androgen receptor activity sustains DNA replication programs in triple-negative breast cancer.}},
author = {Jing Li and Hongwei Yuan and Kefan Chen and Jian Peng and Wu Du and Xinghai Li},
journal = {Cell death \& disease},
year = {2026},
month = aug,
doi = {10.1038/s41419-026-09180-4},
url = {https://europepmc.org/article/MED/42957629},
note = {CC BY},
}
RIS
TY - JOUR
TI - Constitutive androgen receptor activity sustains DNA replication programs in triple-negative breast cancer.
AU - Jing Li
AU - Hongwei Yuan
AU - Kefan Chen
AU - Jian Peng
AU - Wu Du
AU - Xinghai Li
PY - 2026
DA - 2026/08/01
JO - Cell death & disease
DO - 10.1038/s41419-026-09180-4
UR - https://europepmc.org/article/MED/42957629
AB - Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. Despite AR expression in nearly half of TNBCs, androgen receptor signaling inhibitors (ARSIs) have shown minimal clinical benefit. In this study, we utilized HP518, a potent PROTAC that selectively degrades AR, to interrogate the role of AR in TNBC. We uncover a non-canonical, androgen-independent function of AR in AR-positive TNBC cells: AR cooperates with transcriptional regulators FoxA1 and GATA3 to promote expression of DNA replication genes critical for tumor proliferation. Genetic and pharmacological degradation of AR suppresses tumor cell growth, downregulates key DNA replication genes, and disrupts AR-associated transcriptional complexes. In AR-positive TNBC patient-derived xenografts (PDX), HP518 robustly inhibits tumor growth and synergizes with PI3Kα inhibition and chemotherapy. Our findings identify a previously unappreciated mechanism of AR action in TNBC and support AR degradation-not antagonism as a rational therapeutic strategy.
SN - 2041-4889
ER -