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Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive
Sarah Asemota1, Wendy Effah1, Kirsten L Young1
1Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
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.
Insights
This study identifies new triple-negative breast cancer (TNBC) subtypes expressing androgen receptor (AR) and AR splice variants (AR-SVs), particularly in African American women. Targeting AR and JAK-STAT pathways shows promise for treating these aggressive TNBCs.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies.
- The luminal androgen receptor (LAR) subtype, characterized by androgen receptor (AR) expression, represents 15% of TNBC.
- AR splice variants (AR-SVs) further define LAR-TNBC, with distinct clinical correlations.
Purpose of the Study:
- To investigate AR and AR-SV expression in TNBC subtypes.
- To identify potential therapeutic targets within LAR-TNBC.
- To explore the role of AR signaling in TNBC aggressiveness, particularly in African American women.
Main Methods:
- Analysis of AR and AR-SV expression in TNBC patient specimens.
- Subtyping of LAR-TNBC based on AR and AR-SV levels.
- Inhibition studies using selective AR degraders and JAK inhibitors on TNBC cell lines and xenografts.
- Biochemical analysis to elucidate AR and JAK-STAT pathway interactions.
Main Results:
- A significant proportion of TNBC (∼80%) expresses AR, with a subset (∼20%) also expressing AR-SVs.
- Higher AR and AR-SV expression, linked to aggressive phenotypes, are predominantly observed in African American women.
- AR and JAK-STAT signaling pathways are enriched in LAR-TNBC and are crucial for tumor growth.
- Inhibition of AR or JAK signaling suppressed TNBC cell proliferation and tumor growth in preclinical models.
- STAT1 identified as a coactivator of AR.
Conclusions:
- This research identifies novel, pharmacologically targetable subtypes of TNBC.
- The interplay between AR and JAK-STAT signaling represents a promising therapeutic strategy for specific TNBC populations.
- Findings highlight potential disparities in TNBC subtypes and therapeutic vulnerabilities among different ethnic groups.
