Abstract
Induction of estrogen-regulated gene transcription by estrogen receptors ERalpha and ERbeta 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 ERalpha and ERbeta 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, ERbeta 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 ERbeta occupancy of responsive promoters at both estrogen-responsive and AP-1 elements. Ser-87, a conserved mitogen-activated protein kinase site in ERbeta, 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 ERalpha/ERbeta signaling pathways that dictates ER-dependent gene expression and growth of breast cancer cells.
Highlights
Estrogens play a pivotal role in reproductive physiology but are oncogenic in breast cancers
Our findings provide a mechanism by which the CXCR4/stromal cell–derived factor 1 (SDF-1) and ER signaling pathways mutually contribute to a positive autocrine/paracrine feedback loop in breast cancer
Given the ability of the CXCR4/SDF-1 pathway to exert activation of ERh at both estrogen response element (ERE) and activator protein 1 (AP-1) sites regardless of the presence of ER ligands, we evaluated the role of ERh AF-1, and in particular Ser-106 and Ser-124, identified to mediate mouse ERh activation in response to ras and growth factors [5, 7, 16]
Summary
Estrogens play a pivotal role in reproductive physiology but are oncogenic in breast cancers. Regulation of target gene expression by estrogens is mediated through direct interaction with the estrogen receptors ERa and ERh, which belong to the nuclear hormone receptor family of ligand-activated transcription factors [1]. Transcription by ERs involves interaction with their cognate estrogen response element (ERE) within target promoters and tethered interactions with AP-1 transcription factors [2]. The activation function AF-2 located in the COOHterminal region of ERs responds to hormone to initiate a. It is known that in response to many growth factors, such as epidermal growth factor (EGF), insulin-like growth factor I, and heregulins, the activation of ERs is associated with phosphorylation of the AF-1 domain [5,6,7]
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