Products Cited in Publications Worldwide Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive triple-negative breast cancer subtype

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

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; Hollingsworth, T. J.; Fleming, Martin D.; Pritchard, Frances E.; Hendrix, Ashley; Khan, Farhan; Fan, Meiyun; Makowski, Liza; Yin, Zheng; Sasano, Hironobu; Hayes, D. Neil; Pfeffer, Lawrence M.; Miller, Duane D.; Narayanan, Ramesh

DOI: PMID:

Abstract

Triple-neg. 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. Biochem. anal. suggests that STAT1 is an AR coactivator. Collectively, our work identifies pharmacol. targetable TNBC subtypes and identifies growth-promoting interaction between AR and JAK-STAT signaling.

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