Androgen receptor expression is associated with a distinct low-proliferative phenotype in triple-negative breast cancer
Abstract
Background AR-related molecular subtypes, such as the luminal androgen receptor (LAR) subtype, exhibit distinct biological phenotypes in triple-negative breast cancer (TNBC), but the significance of AR expression as a single gene, particularly at single-cell resolution, remains incompletely understood. Methods We analyzed four bulk TNBC cohorts (TCGA, n = 170; METABRIC, n = 335; SCAN-B, n = 174; ORIEN, n = 483) and two single-cell RNA-sequencing cohorts (GSE246613, n = 21; Xu et al., n = 26). Bulk analyses evaluated molecular subtypes, proliferation-related pathways, genomic features, immune-cell abundance, and survival. Single-cell analyses assessed epithelial cell states, pathway activity, cell-cycle characteristics, and cell–cell communication. Results AR-high tumors were enriched for LAR and molecular apocrine subtypes and had lower histologic grade. AR-expressing epithelial cells showed reduced proliferative activity, with greater G1-phase representation and lower S- and G2M-phase activity. Consistently, AR-high tumors showed lower MKI67 expression and reduced proliferation-related pathway activity. AR-high tumors also had fewer TP53 mutations and more PIK3CA mutations. TGFβ-related activity was increased in AR-expressing epithelial cells, while AR-high tumors showed distinct immune-cell composition, including lower estimated Th1/Th2 abundance and higher M2 macrophage abundance. AR expression was not independently associated with survival. Conclusions AR expression identifies a distinct, low-proliferative biological state in TNBC characterized by altered cell-cycle activity, genomic features, enhanced TGFβ-related signaling, and a specific immune-cell composition.
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BibTeX
@misc{kawashima2026androgen,
title = {{Androgen receptor expression is associated with a distinct low-proliferative phenotype in triple-negative breast cancer}},
author = {Kei KAWASHIMA and Reika Matsushita and Eslam A. Elsaedy and Amanda Copeland and Masanori Oshi and Akimitsu Yamada and Kazutaka Narui and Takashi Ishikawa and Itaru Endo and Kazuaki Takabe},
howpublished = {Research Square},
year = {2026},
month = nov,
doi = {10.21203/rs.3.rs-11368679/v1},
url = {https://doi.org/10.21203/rs.3.rs-11368679/v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - Androgen receptor expression is associated with a distinct low-proliferative phenotype in triple-negative breast cancer
AU - Kei KAWASHIMA
AU - Reika Matsushita
AU - Eslam A. Elsaedy
AU - Amanda Copeland
AU - Masanori Oshi
AU - Akimitsu Yamada
AU - Kazutaka Narui
AU - Takashi Ishikawa
AU - Itaru Endo
AU - Kazuaki Takabe
PY - 2026
DA - 2026/11/01
PB - Research Square
DO - 10.21203/rs.3.rs-11368679/v1
UR - https://doi.org/10.21203/rs.3.rs-11368679/v1
AB - Background AR-related molecular subtypes, such as the luminal androgen receptor (LAR) subtype, exhibit distinct biological phenotypes in triple-negative breast cancer (TNBC), but the significance of AR expression as a single gene, particularly at single-cell resolution, remains incompletely understood. Methods We analyzed four bulk TNBC cohorts (TCGA, n = 170; METABRIC, n = 335; SCAN-B, n = 174; ORIEN, n = 483) and two single-cell RNA-sequencing cohorts (GSE246613, n = 21; Xu et al., n = 26). Bulk analyses evaluated molecular subtypes, proliferation-related pathways, genomic features, immune-cell abundance, and survival. Single-cell analyses assessed epithelial cell states, pathway activity, cell-cycle characteristics, and cell–cell communication. Results AR-high tumors were enriched for LAR and molecular apocrine subtypes and had lower histologic grade. AR-expressing epithelial cells showed reduced proliferative activity, with greater G1-phase representation and lower S- and G2M-phase activity. Consistently, AR-high tumors showed lower MKI67 expression and reduced proliferation-related pathway activity. AR-high tumors also had fewer TP53 mutations and more PIK3CA mutations. TGFβ-related activity was increased in AR-expressing epithelial cells, while AR-high tumors showed distinct immune-cell composition, including lower estimated Th1/Th2 abundance and higher M2 macrophage abundance. AR expression was not independently associated with survival. Conclusions AR expression identifies a distinct, low-proliferative biological state in TNBC characterized by altered cell-cycle activity, genomic features, enhanced TGFβ-related signaling, and a specific immune-cell composition.
SN - 2693-5015
ER -