Progesterone Receptor Attenuates STAT1-Mediated IFN Signaling in Breast Cancer.

Abstract

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.

• Authors: Merit L Goodman, Gloria M Trinca, Katherine R Walter, Evangelia K Papachristou, Clive S D'Santos, Tianbao Li, Qi Liu, Zhao Lai, Prabhakar Chalise, Rashna Madan, Fang Fan, Mary A Markiewicz, Victor X Jin, Jason S Carroll, Christy R Hagan
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 202 Issue 10 Pg. 3076-3086 (05 15 2019) ISSN: 1550-6606 [Electronic] United States
• PMID: 30936295 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019 by The American Association of Immunologists, Inc.

Chemical References

• IFNG protein, human
• Neoplasm Proteins
• Receptors, Progesterone
• STAT1 Transcription Factor
• STAT1 protein, human
• Interferon-gamma

Topics

• Breast Neoplasms (genetics, immunology)
• Cell Line, Tumor
• Female
• Humans
• Interferon-gamma (genetics, immunology)
• Neoplasm Proteins (genetics, immunology)
• Phosphorylation (genetics, immunology)
• Receptors, Progesterone (genetics, immunology)
• STAT1 Transcription Factor (genetics, immunology)
• Tumor Escape