Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive triple-negative breast cancer subtype
Sarah Asemota, Wendy Effah, Kirsten Young, Jeremiah Holt, Linnea Cripe, Suriyan Ponnusamy, Thirumagal Thiyagarajan, Dong‐Jin Hwang, Yali He, Keely May McNamara, Daniel L. Johnson, Yinan Wang, Brandy Grimes, Yekta Khosrosereshki, TJ Hollingsworth, Martin D. Fleming, F. Elizabeth Pritchard, Ashley Hendrix, Farhan Khan, Meiyun Fan, Liza Makowski, Zheng Yin, Hironobu Sasano, D. Neil Hayes, Lawrence M. Pfeffer, Duane D. Miller, Ramesh Narayanan
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.