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

Induction of estrogen-regulated gene transcription by estrogen receptors ERA and ERB plays an important role in breast cancer development and growth. High expression of the chemokine receptor CXCR4and 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 CXCR4silencing and, conversely, estrogen-induced gene expression and growth of MCF-7 cells were impaired on CXCR4inhibition. Both ERA and ERB were activated by SDF-1 in the presence of CXCR4and by overexpression of a constitutively active CXCR4, indicating that CXCR4 signals to both receptors. In particular, ERB 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 ERB occupancy of responsive promoters at both estrogen-responsive and AP-1 elements. Ser-87, a conserved mitogen-activated protein kinase site in ERB, was highly phosphorylated by SDF-1, revealing an essential role of the AF-1 domain in response to CXCR4activation. These results identify a complete autocrine loop between the CXCR4/SDF-1 and ERA/ERB signaling pathways that dictates ER-dependent gene expression and growth of breast cancer cells. [Cancer Res 2009;69(14):5793–800]