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

Induction of estrogen-regulated gene transcription by estrogen receptors ER alpha and ER beta 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 I (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 alpha and EP beta 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 beta was able to translate the effects of SDF-1 on its own expression, as well as enhance activator protein I (AP-1) containing genes cyclin D1 and c-Myc in the presence of tamoxifen. This correlated with an increased ER beta occupancy of responsive promoters at both estrogen-responsive and AP-1 elements. Ser-87, a conserved mitogen-activated protein kinase site in ER beta, 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 alpha/ER beta signaling pathways that dictates ER-dependent gene expression and growth of breast cancer cells. [Cancer Res 2009;69(14):5793-800]