Open AccessFeedback control of the CXCR 7/ CXCL 11 chemokine axis by estrogen receptor α in ovarian cancer
Author(s) -
Benhadjeba Samira,
Edjekouane Lydia,
Sauvé Karine,
Carmona Euridice,
Tremblay André
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12362
Subject(s) - estrogen , estrogen receptor , cancer research , chemokine receptor , stromal cell , biology , chemokine , downregulation and upregulation , estrogen receptor alpha , microbiology and biotechnology , endocrinology , immunology , cancer , breast cancer , inflammation , gene , biochemistry , genetics
Ovarian cancer (OC) is one of the most intractable diseases, exhibiting tremendous molecular heterogeneity and lacking reliable methods for screening, resulting in late diagnosis and widespread peritoneal dissemination. Menopausal estrogen replacement therapy is a well‐recognized risk factor for OC, but little is known about how estrogen might contribute to this disease at the cellular level. This study identifies chemokine receptor CXCR 7/ ACKR 3 as an estrogen‐responsive gene, whose expression is markedly enhanced by estrogen through direct recruitment of ER α and transcriptional active histone modifications in OC cells. The gene encoding CXCR 7 chemokine ligand I‐ TAC / CXCL 11 was also upregulated by estrogen, resulting in Ser‐118 phosphorylation, activation, and recruitment of estrogen receptor ER α at the CXCR 7 promoter locus for positive feedback regulation. Both CXCR 7 and CXCL 11, but not CXCR 3 (also recognized to interact with CXCL 11), were found to be significantly increased in stromal sections of microdissected tumors and positively correlated in mesenchymal subtype of OC. Estrogenic induction of mesenchymal markers SNAI 1, SNAI 2, and CDH 2 expression, with a consequent increase in cancer cell migration, was shown to depend on CXCR 7, indicating a key role for CXCR 7 in mediating estrogen upregulation of mesenchymal markers to induce invasion of OC cells. These findings identify a feed‐forward mechanism that sustains activation of the CXCR 7/ CXCL 11 axis under ER α control to induce the epithelial–mesenchymal transition pathway and metastatic behavior of OC cells. Such interplay underlies the complex gene profile heterogeneity of OC that promotes changes in tumor microenvironment and metastatic acquisition.