TY - JOUR
T1 - Progesterone receptor attenuates STAT1-mediated IFN signaling in breast cancer
AU - Goodman, Merit L.
AU - Trinca, Gloria M.
AU - Walter, Katherine R.
AU - Papachristou, Evangelia K.
AU - D’Santos, Clive S.
AU - Li, Tianbao
AU - Liu, Qi
AU - Lai, Zhao
AU - Chalise, Prabhakar
AU - Madan, Rashna
AU - Fan, Fang
AU - Markiewicz, Mary A.
AU - Jin, Victor X.
AU - Carroll, Jason S.
AU - Hagan, Christy R.
N1 - Funding Information:
This work was supported by the National Cancer Institute (NCI) R00CA166643 (to C.R.H.), Department of Defense Breast Cancer Research Program W81XWH-16-1-0320 (to C.R.H.), Susan G. Komen Foundation CCR16376147 (to C.R.H.), V Foundation V2015-025 (to C.R.H.), National Institutes of Health R01GM114142 (to V.X.J.), U54CA217297 (to V.X.J.), and 1S10OD021805-01 (to Z.L.), the Owens
Funding Information:
This work was supported by the National Cancer Institute (NCI) R00CA166643 (to C.R.H.), Department of Defense Breast Cancer Research Program W81XWH-16-1-0320 (to C.R.H.), Susan G. Komen Foundation CCR16376147 (to C.R.H.), V Foundation V2015-025 (to C.R.H.), National Institutes of Health R01GM114142 (to V.X.J.), U54CA217297 (to V.X.J.), and 1S10OD021805-01 (to Z.L.), the Owens Foundation (to V.X.J.), and NCI Cancer Center Support Grant P30 CA168524 (to C.R.H.). We thank Jade Hall and Katelin Gibson for technical support. We acknowledge support from the University of Kansas Cancer Center’s Biospecimen Repository Core Facility staff, in particular Tara Meyer, for helping obtain human specimens and for performing histological work.
Funding Information:
We thank Jade Hall and Katelin Gibson for technical support. We acknowledge support from the University of Kansas Cancer Center’s Biospecimen Repository Core Facility staff, in particular Tara Meyer, for helping obtain human specimens and for performing histological work.
Publisher Copyright:
Copyright © 2019 by The American Association of Immunologists, Inc.
PY - 2019/5/15
Y1 - 2019/5/15
N2 - Why some tumors remain indolent and others progress to clinical relevance remains a major unanswered question in cancer biology. IFN signaling in nascent tumors, mediated by STAT1, is a critical step through which the surveilling immune system can recognize and destroy developing tumors. In this study, we have identified an interaction between the progesterone receptor (PR) and STAT1 in breast cancer cells. This interaction inhibited efficient IFN-induced STAT1 phosphorylation, as we observed a decrease in phospho-STAT1 in response to IFN treatment in PR-positive breast cancer cell lines. This phenotype was further potentiated in the presence of PR ligand. In human breast cancer samples, PR-positive tumors exhibited lower levels of phospho-STAT1 as compared with their PR-negative counterparts, indicating that this phenotype translates to human tumors. Breast cancer cells lacking PR exhibited higher levels of IFN-stimulated gene (ISG) RNA, the transcriptional end point of IFN activation, indicating that unliganded PR alone could decrease transcription of ISGs. Moreover, the absence of PR led to increased recruitment of STAT1, STAT2, and IRF9 (key transcription factors necessary for ISG transcription) to ISG promoters. These data indicate that PR, both in the presence and absence of ligand, attenuates IFN-induced STAT1 signaling, culminating in significantly abrogated activation of genes transcribed in response to IFNs. PR-positive tumors may use downregulation of STAT1-mediated IFN signaling to escape immune surveillance, leading to the development of clinically relevant tumors. Selective immune evasion of PR-positive tumors may be one explanation as to why over 65% of breast cancers are PR positive at the time of diagnosis.
AB - Why some tumors remain indolent and others progress to clinical relevance remains a major unanswered question in cancer biology. IFN signaling in nascent tumors, mediated by STAT1, is a critical step through which the surveilling immune system can recognize and destroy developing tumors. In this study, we have identified an interaction between the progesterone receptor (PR) and STAT1 in breast cancer cells. This interaction inhibited efficient IFN-induced STAT1 phosphorylation, as we observed a decrease in phospho-STAT1 in response to IFN treatment in PR-positive breast cancer cell lines. This phenotype was further potentiated in the presence of PR ligand. In human breast cancer samples, PR-positive tumors exhibited lower levels of phospho-STAT1 as compared with their PR-negative counterparts, indicating that this phenotype translates to human tumors. Breast cancer cells lacking PR exhibited higher levels of IFN-stimulated gene (ISG) RNA, the transcriptional end point of IFN activation, indicating that unliganded PR alone could decrease transcription of ISGs. Moreover, the absence of PR led to increased recruitment of STAT1, STAT2, and IRF9 (key transcription factors necessary for ISG transcription) to ISG promoters. These data indicate that PR, both in the presence and absence of ligand, attenuates IFN-induced STAT1 signaling, culminating in significantly abrogated activation of genes transcribed in response to IFNs. PR-positive tumors may use downregulation of STAT1-mediated IFN signaling to escape immune surveillance, leading to the development of clinically relevant tumors. Selective immune evasion of PR-positive tumors may be one explanation as to why over 65% of breast cancers are PR positive at the time of diagnosis.
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U2 - 10.4049/jimmunol.1801152
DO - 10.4049/jimmunol.1801152
M3 - Article
C2 - 30936295
AN - SCOPUS:85065678009
VL - 202
SP - 3076
EP - 3086
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 10
ER -