Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive triple-negative breast cancer subtype
Document Type
Article
Publication Date
12-26-2023
Publication Title
Cell Reports
Volume
42
Issue
12
Funding Sponsor
U.S. Department of Defense
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype with no targeted therapeutics. The luminal androgen receptor (LAR) subtype constitutes 15% of TNBC and is enriched for androgen receptor (AR) and AR target genes. Here, we show that a cohort of TNBC not only expresses AR at a much higher rate (∼80%) but also expresses AR splice variants (AR-SVs) (∼20%), further subclassifying LAR-TNBC. Higher AR and AR-SV expression and corresponding aggressive phenotypes are observed predominantly in specimens obtained from African American women. LAR TNBC specimens are enriched for interferon, Janus kinase (JAK)-signal activator and transducer (STAT), and androgen signaling pathways, which are exclusive to AR-expressing epithelial cancer cells. AR- and AR-SV-expressing TNBC cell proliferation and xenograft and patient-tumor explant growth are inhibited by AR N-terminal domain-binding selective AR degrader or by a JAK inhibitor. Biochemical analysis suggests that STAT1 is an AR coactivator. Collectively, our work identifies pharmacologically targetable TNBC subtypes and identifies growth-promoting interaction between AR and JAK-STAT signaling.
Recommended Citation
Asemota, Sarah; Effah, Wendy; Young, Kirsten L.; Holt, Jeremiah; Cripe, Linnea; Ponnusamy, Suriyan; Thiyagarajan, Thirumagal; Hwang, Dong Jin; He, Yali; Mcnamara, Keely; Johnson, Daniel; Wang, Yinan; Grimes, Brandy; Khosrosereshki, Yekta; and Hollingsworth, T. J., "Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive triple-negative breast cancer subtype" (2023). Faculty Publications. 1. 10.1016/j.celrep.2023.113461
https://dc.uthsc.edu/fac_pubs/1