TY - JOUR
T1 - Interferon-stimulated genes are transcriptionally repressed by PR in breast cancer
AU - Walter, Katherine R.
AU - Goodman, Merit L.
AU - Singhal, Hari
AU - Hall, Jade A.
AU - Li, Tianbao
AU - Holloran, Sean M.
AU - Trinca, Gloria M.
AU - Gibson, Katelin A.
AU - Jin, Victor X.
AU - Greene, Geoffrey L.
AU - Hagan, Christy R.
N1 - Funding Information:
This work was supported by NCI R00CA166643 (to C.R. Hagan), DOD BCRP W81XWH-16-1-0320 (to C.R. Hagan), Susan G Komen Foundation CCR16376147 (to C.R. Hagan), V Foundation V2015-025 (to C.R. Hagan), and the NCI Cancer Center Support Grant P30 CA168524 (to C.R. Hagan).
PY - 2017/10/1
Y1 - 2017/10/1
N2 - The progesterone receptor (PR) regulates transcriptional programs that drive proliferation, survival, and stem cell phenotypes. Although the role of native progesterone in the development of breast cancer remains controversial, PR clearly alters the transcriptome in breast tumors. This study identifies a class of genes, Interferon (IFN)-stimulated genes (ISGs), potently downregulated by ligand-activated PR which have not been previously shown to be regulated by PR. Progestin-dependent transcriptional repression of ISGs was observed in breast cancer cell line models and human breast tumors. Ligand-independent regulation of ISGs was also observed, as basal transcript levels were markedly higher in cells with PR knockdown. PR repressed ISG transcription in response to IFN treatment, the canonical mechanism through which these genes are activated. Liganded PR is robustly recruited to enhancer regions of ISGs, and ISG transcriptional repression is dependent upon PR's ability to bind DNA. In response to PR activation, key regulatory transcription factors that are required for IFN-activated ISG transcription, STAT2 and IRF9, exhibit impaired recruitment to ISG promoter regions, correlating with PR/ligand-dependent ISG transcriptional repression. IFN activation is a critical early step in nascent tumor recognition and destruction through immunosurveillance. As the large majority of breast tumors are PR positive at the time of diagnosis, PR-dependent downregulation of IFN signaling may be a mechanism through which early PR-positive breast tumors evade the immune system and develop into clinically relevant tumors.
AB - The progesterone receptor (PR) regulates transcriptional programs that drive proliferation, survival, and stem cell phenotypes. Although the role of native progesterone in the development of breast cancer remains controversial, PR clearly alters the transcriptome in breast tumors. This study identifies a class of genes, Interferon (IFN)-stimulated genes (ISGs), potently downregulated by ligand-activated PR which have not been previously shown to be regulated by PR. Progestin-dependent transcriptional repression of ISGs was observed in breast cancer cell line models and human breast tumors. Ligand-independent regulation of ISGs was also observed, as basal transcript levels were markedly higher in cells with PR knockdown. PR repressed ISG transcription in response to IFN treatment, the canonical mechanism through which these genes are activated. Liganded PR is robustly recruited to enhancer regions of ISGs, and ISG transcriptional repression is dependent upon PR's ability to bind DNA. In response to PR activation, key regulatory transcription factors that are required for IFN-activated ISG transcription, STAT2 and IRF9, exhibit impaired recruitment to ISG promoter regions, correlating with PR/ligand-dependent ISG transcriptional repression. IFN activation is a critical early step in nascent tumor recognition and destruction through immunosurveillance. As the large majority of breast tumors are PR positive at the time of diagnosis, PR-dependent downregulation of IFN signaling may be a mechanism through which early PR-positive breast tumors evade the immune system and develop into clinically relevant tumors.
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U2 - 10.1158/1541-7786.MCR-17-0180
DO - 10.1158/1541-7786.MCR-17-0180
M3 - Article
C2 - 28684637
AN - SCOPUS:85030481734
VL - 15
SP - 1331
EP - 1340
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 10
ER -