Positive Feedback Activation of Estrogen Receptors by the CXCL12-CXCR4 Pathway

¹Research Center, CHU Ste-Justine, and Departments of ²Biochemistry and ³Obstetrics and Gynecology, University of Montreal, Montréal, Quebec, Canada

^* To whom correspondence should be addressed. E-mail: andre.tremblay.1{at}umontreal.ca.

	Abstract

Induction of estrogen-regulated gene transcription by estrogen receptors ER and ER plays an important role in breast cancer development and growth. High expression of the chemokine receptor CXCR4 and its ligand CXCL12/stromal cell-derived factor 1 (SDF-1) has also been correlated with aggressive breast tumor phenotypes. Here, we describe a positive regulatory loop between the CXCR4/SDF-1 signaling pathway and ER transcriptional competence in human breast cancer cells. Treatment of breast carcinoma MCF-7 cells with SDF-1 increased ER transcriptional activity and expression of ER target genes, including SDF-1 itself. These effects were blocked by the antiestrogen ICI-182780 and by CXCR4 silencing and, conversely, estrogen-induced gene expression and growth of MCF-7 cells were impaired on CXCR4 inhibition. Both ER and ER were activated by SDF-1 in the presence of CXCR4 and by overexpression of a constitutively active CXCR4, indicating that CXCR4 signals to both receptors. In particular, ER was able to translate the effects of SDF-1 on its own expression, as well as enhance activator protein 1 (AP-1) containing genes cyclin D1 and c-Myc in the presence of tamoxifen. This correlated with an increased ER occupancy of responsive promoters at both estrogen-responsive and AP-1 elements. Ser-87, a conserved mitogen-activated protein kinase site in ER, was highly phosphorylated by SDF-1, revealing an essential role of the AF-1 domain in response to CXCR4 activation. These results identify a complete autocrine loop between the CXCR4/SDF-1 and ER/ER signaling pathways that dictates ER-dependent gene expression and growth of breast cancer cells. [Cancer Res 2009;69(14):5793–800]

Key Words: estrogen receptor, ER, ER, AF-1, AF-2, stromal cell–derived factor 1, SDF-1, chemokine receptor, MAPK/Erk, MCF-7, breast cancer