@article{e7b07f89da144f229df578bc0013d85e,
title = "Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive triple-negative breast cancer subtype",
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.",
keywords = "AR, AR splice variant, AR-SV, AR-V7, CP: Cancer, JAK STAT pathway, LAR TNBC, SARD, TNBC, androgen receptor, coactivator, luminal androgen receptor TNBC, ruxolitinib, selective AR degrader, triple-negative breast cancer",
author = "Sarah Asemota and Wendy Effah and Young, {Kirsten L.} and Jeremiah Holt and Linnea Cripe and Suriyan Ponnusamy and Thirumagal Thiyagarajan and Hwang, {Dong Jin} and Yali He and Keely Mcnamara and Daniel Johnson and Yinan Wang and Brandy Grimes and Yekta Khosrosereshki and Hollingsworth, {T. J.} and Fleming, {Martin D.} and Pritchard, {Frances E.} and Ashley Hendrix and Farhan Khan and Meiyun Fan and Liza Makowski and Zheng Yin and Hironobu Sasano and Hayes, {D. Neil} and Pfeffer, {Lawrence M.} and Miller, {Duane D.} and Ramesh Narayanan",
note = "Funding Information: The authors thank the NCI Division of Cancer Treatment and Diagnosis Stepping Stones program for assistance in acquiring compound and in vitro ADME data for the development of UT-105. This work was supported by research grants from the National Cancer Institute ( R01-CA229164 , R01-CA253329 , and F30CA265224 ), the Department of Defense (DOD; W81XWH-21-1-0055 ), Oncternal Therapeutics Inc., San Diego, CA , Eric Muirhead Chair of Excellence , and the UTHSC Center for Cancer Research . Funding Information: The authors thank the NCI Division of Cancer Treatment and Diagnosis Stepping Stones program for assistance in acquiring compound and in vitro ADME data for the development of UT-105. This work was supported by research grants from the National Cancer Institute (R01-CA229164, R01-CA253329, and F30CA265224), the Department of Defense (DOD; W81XWH-21-1-0055), Oncternal Therapeutics Inc. San Diego, CA, Eric Muirhead Chair of Excellence, and the UTHSC Center for Cancer Research. R.N. provided the overall supervision of the project. S.A. Z.Y. H.S. L.M.P. D.D.M. and R.N. contributed to conceptualization of different parts of the project. S.A. W.E. K.L.Y. S.P. T.T. K.M. Y.W. T.J.H. and Y.K. contributed to experiment design and/or experimentation. D.-J.H. Y.H. B.G. M.D.F. F.E.P. and A.H. provided critical resources for the project. J.H. L.C. D.J. B.G. Z.Y. F.K. L.M. D.N.H. and M.F. contributed to data analysis. R.N. and S.A. wrote the manuscript, and the remaining authors reviewed and edited the manuscript to generate the final version. R.N. is a consultant to Oncternal Therapeutics. The SARDs mentioned in this manuscript are licensed to Oncternal Therapeutics Inc. San Diego, CA, by the University of Tennessee Research Foundation (UTRF) under an exclusive licensing agreement. S.P. D.J.H. Y.H. D.D.M. and R.N. are co-inventors in patents related to UT-105 and receive royalties. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = dec,
day = "26",
doi = "10.1016/j.celrep.2023.113461",
language = "English (US)",
volume = "42",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "12",
}