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Sci Rep. 2017 Dec 11;7(1):17289. doi: 10.1038/s41598-017-17102-w.

Oestrogen Receptor-α binds the FOXP3 promoter and modulates regulatory T-cell function in human cervical cancer.

Author information

1
Department of Microbiology, Kidwai Memorial Institute of Oncology, Bangalore, India.
2
Shodhaka Life Sciences Private Limited, Bangalore, India.
3
Structural Biology Lab, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, India.
4
Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore, India.
5
Department of Histopathology, Tata Medical Center, Kolkata, India.
6
National Center for Biological Sciences, TIFR, Bangalore, India.
7
Institute of Bioinformatics And Applied Biotechnology, Bangalore, India.
8
Department of Gynecology, Kidwai Memorial Institute of Oncology, Bangalore, India.
9
Department of Immunohematology, Kidwai Memorial Institute of Oncology, Bangalore, India.
10
Department of Transfusion Medicine, JIPMER, Puducherry, India.
11
Department of Microbiology, Kidwai Memorial Institute of Oncology, Bangalore, India. microjayshree@gmail.com.

Abstract

Oestrogen controls Foxp3 expression in regulatory T cells (Treg cells) via a mechanism thought to involve oestrogen receptor alpha (ERα), but the molecular basis and functional impact of ERα signalling in Treg cells remain unclear. We report that ERα ligand oestradiol (E2) is significantly increased in human cervical cancer (CxCa) tissues and tumour-infiltrating Treg cells (CD4+CD25hiCD127low), whereas blocking ERα with the antagonist ICI 182,780 abolishes FOXP3 expression and impairs the function of CxCa infiltrating Treg cells. Using a novel approach of co-immunoprecipitation with antibodies to E2 for capture, we identified binding of E2:ERα complexes to FOXP3 protein in CxCa-derived Treg cells. Chromatin immunoprecipitation analyses of male blood Treg cells revealed ERα occupancy at the FOXP3 promoter and conserved non-coding DNA elements 2 and 3. Accordingly, computational analyses of the enriched regions uncovered eight putative oestrogen response elements predicted to form a loop that can activate the FOXP3 promoter. Together, these data suggest that E2-mediated ERα signalling is critical for the sustenance of FOXP3 expression and Treg cell function in human CxCa via direct interaction of ERα with FOXP3 promoter. Overall, our work gives a molecular insight into ERα signalling and highlights a fundamental role of E2 in controlling human Treg cell physiology.

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