Cell Reports (Dec 2023)
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 L. Young,
- Jeremiah Holt,
- Linnea Cripe,
- Suriyan Ponnusamy,
- Thirumagal Thiyagarajan,
- Dong-Jin Hwang,
- Yali He,
- Keely Mcnamara,
- Daniel Johnson,
- Yinan Wang,
- Brandy Grimes,
- Yekta Khosrosereshki,
- T.J. Hollingsworth,
- Martin D. Fleming,
- Frances E. Pritchard,
- Ashley Hendrix,
- Farhan Khan,
- Meiyun Fan,
- Liza Makowski,
- Zheng Yin,
- Hironobu Sasano,
- D. Neil Hayes,
- Lawrence M. Pfeffer,
- Duane D. Miller,
- Ramesh Narayanan
Affiliations
- Sarah Asemota
- Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Wendy Effah
- Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Kirsten L. Young
- Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Jeremiah Holt
- Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Linnea Cripe
- Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Suriyan Ponnusamy
- Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Thirumagal Thiyagarajan
- Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Dong-Jin Hwang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Yali He
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Keely Mcnamara
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8577, Japan
- Daniel Johnson
- Molecular Bioinformatics Core, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Yinan Wang
- Department of Pathology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Brandy Grimes
- West Cancer Center and Research Institute, Memphis, TN 38138, USA
- Yekta Khosrosereshki
- Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- T.J. Hollingsworth
- Department of Ophthalmology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Martin D. Fleming
- Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Frances E. Pritchard
- Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Ashley Hendrix
- Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Farhan Khan
- Department of Pathology, Methodist Hospital, Memphis, TN 38104, USA
- Meiyun Fan
- Department of Pathology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Liza Makowski
- Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA; UTHSC Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Zheng Yin
- Biomedical and Informatics Services Core, Houston Methodist Research Institute, Houston, TX 77030, USA
- Hironobu Sasano
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8577, Japan
- D. Neil Hayes
- Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA; UTHSC Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Lawrence M. Pfeffer
- Department of Pathology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA; UTHSC Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Duane D. Miller
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38103, USA; UTHSC Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Ramesh Narayanan
- Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA; UTHSC Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38103, USA; Corresponding author
- Journal volume & issue
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Vol. 42,
no. 12
p. 113461
Abstract
Summary: 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.
