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

Abstract

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 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 ERA and ERB 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, 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 CXCR4 activation. 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.

Chemokines in cancer related inflammation

“…Estrogens increase the expression of CXCL12; activation of the CXCR4/ CXCL12 signalling pathway, in turn, promotes estrogen receptor transcriptional activity [82]. In human glioblastoma cells, activation of the formyl-peptide chemotactic receptor (a non-chemokine receptor) resulted in the phosphorylation of Epidermal Growth Factor Receptor.…”

Inflammatory events in endometrial adenocarcinoma

“…Elevated expression of CXCR4 in endometrial adenocarcinoma was also examined in a nude mouse xenograft model, and found to lead to a significantly higher incidence of metastases (Gelmini et al 2009). Notably, a recent study provides evidence for an autocrine loop between the CXCR4/SDF1 and ESR1/ ESR2 signalling pathways, which alters growth of breast cancer cells (Sauve et al 2009), and it will be interesting to see if the same applies to endometrial cancers. Other members of the CXC chemokine family, CXCL1 and IL8 (also known as CXCL8), are elevated in endometrial adenocarcinoma (Berry et al 2001, Wallace et al 2009).…”

189 HIV Tropism and Decreased Risk of Breast Cancer

“…In addition to the reported induction of apoptosis, [10] induction of various growth factors could contribute to or account for the association. [7][8][9] Our study was very small and limited to U.S. women who may not be representative of the global HIV epidemic. In our evaluation of classical breast cancer risk factors, we observed a lower risk associated with menopause.…”

“…However, derivative studies should also consider indirect pathways, such as blockade of pro-carcinogenic effects of chemokines expressed by tumor-infiltrating macrophages [17]. Continued studies of molecular interactions [8][9][10], of patients with malignancies, and of populations at risk for these diseases are needed to develop insight into the roles of CXCR4 in breast and other cancers, which may lead to new approaches for prevention or treatment. Figure S1 The Trofile Assay: RNA from patient plasma is subjected to RT-PCR amplification to obtain a broad representation of envelope (env) genes from HIV populations.…”

“…CXCR4 may play an essential role in metastasis and, indirectly, earlier stages of tumor growth [4,5,[7][8][9]. Linking HIV with breast cancer was the observation that programmed cell death (apoptosis) was induced in human breast cancer cell lines through binding of CXCR4-tropic, but not CCR5-tropic, HIV envelope protein [10].…”