Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive triple-negative breast cancer subtype.

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. [Display omitted] • Luminal androgen receptor (LAR) TNBC specimens express AR splice variants (AR-SVs) • AR-SV promotes aggressive TNBC growth • AR-positive/AR-SV-positive specimens activate interferon JAK-STAT • N terminus AR degrader effective in AR- and AR-SV-positive TNBC xenografts Asemota et al. show that TNBC specimens, notably from African American women, express androgen receptor splice variants (AR-SVs), and AR-SV expression causes aggressive TNBC growth. AR- and AR-SV-positive TNBC specimens are enriched for JAK-STAT signaling. Growth of AR- and AR-SV-positive TNBC xenografts is inhibited by AR N terminus domain-binding degrader. [ABSTRACT FROM AUTHOR]