Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive triple-negative breast cancer subtype
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 muc...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723014730 |
| _version_ | 1827739838599659520 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Sarah Asemota |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T03:13:43Z |
| format | Article |
| id | doaj.art-ac241ea52bf347e5b56f2020cc95e398 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-11T03:13:43Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-ac241ea52bf347e5b56f2020cc95e3982023-11-18T04:28:34ZengElsevierCell Reports2211-12472023-12-014212113461Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive triple-negative breast cancer subtypeSarah Asemota0Wendy Effah1Kirsten L. Young2Jeremiah Holt3Linnea Cripe4Suriyan Ponnusamy5Thirumagal Thiyagarajan6Dong-Jin Hwang7Yali He8Keely Mcnamara9Daniel Johnson10Yinan Wang11Brandy Grimes12Yekta Khosrosereshki13T.J. Hollingsworth14Martin D. Fleming15Frances E. Pritchard16Ashley Hendrix17Farhan Khan18Meiyun Fan19Liza Makowski20Zheng Yin21Hironobu Sasano22D. Neil Hayes23Lawrence M. Pfeffer24Duane D. Miller25Ramesh Narayanan26Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USADepartment of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USADepartment of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USADepartment of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USADepartment of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USADepartment of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USADepartment of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38103, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38103, USADepartment of Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8577, JapanMolecular Bioinformatics Core, University of Tennessee Health Science Center, Memphis, TN 38103, USADepartment of Pathology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USAWest Cancer Center and Research Institute, Memphis, TN 38138, USADepartment of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USADepartment of Ophthalmology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USADepartment of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USADepartment of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USADepartment of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USADepartment of Pathology, Methodist Hospital, Memphis, TN 38104, USADepartment of Pathology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USADepartment 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, USABiomedical and Informatics Services Core, Houston Methodist Research Institute, Houston, TX 77030, USADepartment of Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8577, JapanDepartment 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, USADepartment 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, USADepartment 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, USADepartment 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723014730CP: Cancer |
| spellingShingle | 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 Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive triple-negative breast cancer subtype Cell Reports CP: Cancer |
| title | Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive triple-negative breast cancer subtype |
| title_full | Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive triple-negative breast cancer subtype |
| title_fullStr | Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive triple-negative breast cancer subtype |
| title_full_unstemmed | Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive triple-negative breast cancer subtype |
| title_short | Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive triple-negative breast cancer subtype |
| title_sort | identification of a targetable jak stat enriched androgen receptor and androgen receptor splice variant positive triple negative breast cancer subtype |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723014730 |
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