Stromal Cell-Derived Factor 1, a Novel Target of Estrogen Receptor Action, Mediates the Mitogenic Effects of Estradiol in Ovarian and Breast Cancer Cells

Abstract

Recent clinical studies estimate that 60-70% of human ovarian and breast cancers overexpress the estrogen receptor (ER). However, despite the established mitogenic effects of estrogen in these tumors, proliferative markers of hormone action are limited. In the current study, we report that the growth stimulatory cytokine stromal cell-derived factor 1 (SDF-1) is a bona fide target of estrogen action in ERalpha-positive human ovarian and breast cancer cells. Notably, estradiol treatment of BG-1 (ovarian carcinoma) and MCF-7 (breast carcinoma) cells leads to rapid and robust induction of the SDF-1alpha and beta isoforms. This response is blocked by the pure ER antagonist ICI 182,780 and is not apparent in ER-negative ovarian cells, indicating that SDF-1 regulation is ERalpha mediated. Treatment with the protein synthesis inhibitor cycloheximide had no effect on estradiol induction of induction of SDF-1 mRNA levels mRNA levels, demonstrating that SDF-1 is a direct target of ERalpha. SDF-1 protein levels, although undetectable under basal conditions, were strikingly increased by hormone both intracellularly and in the media of cultured BG-1 and MCF-7 cells. In cell proliferation assays, the mitogenic effects of estradiol were neutralized by addition of an SDF-1 antibody and mimicked by the addition of exogenous SDF-1 protein, indicating that SDF-1 mediates the proliferative actions of hormone. Furthermore, activation of the SDF-1 receptor CXCR4 stimulated BG-1 and MCF-7 cell proliferation in a manner comparable to estradiol. Taken together, these results demonstrate a novel estrogen-mediated paracrine pathway for inducing cancer cell proliferation and suggest that SDF-1 and CXCR4 may represent novel therapeutic targets in ERalpha-positive ovarian and breast tumors.

A genome-wide study of the repressive effects of estrogen receptor beta on estrogen receptor alpha signaling in breast cancer cells

“…Several previously known ERa-regulated genes were detected in this study, for example, TFF1/pS2 (FC 34.8), GREB1 (FC B8 for three transcript variants), SIAH 2 (FC 5.3), SDF1/CXCL12 (FC 5.6), IGFBP-4 (FC 5.5), CCNA2 (FC 4.2), STC2 (FC 2.3), PR (FC 1.9), RBBP-8 (FC 1.7), NRIP1/RIP140 (FC 1.7), CTSD (FC 1.6) and NR5A2/LRH1 (FC 1.7), all confirming the data previously published (Roberts et al, 1988;Inoue et al, 2002;Hall and Korach, 2003;Annicotte et al, 2005;Frasor et al, 2005). Also downregulated genes such as ERa itself (FC 0. by ERa and decrease of S100A6/calcyclin by ERb correlates to the earlier findings of in vivo gene expression in wt and ER knockout mouse bone tissue (Lindberg et al, 2003).…”

The pleiotropic effects of the SDF-1–CXCR4 axis in organogenesis, regeneration and tumorigenesis

“…Supporting this notion, it has been recently reported that several CXCR4 þ cancers (e.g., breast, ovarian, prostate cancers, as well as rhabdomyosarcoma and neuroblastoma) metastasize to the bones and lymph nodes in an SDF-1-dependent manner. [55][56][57][58][59] As mentioned, CXCR4 is also expressed on cells from several hematopoietic malignancies. For example, the SDF-1-CXCR4 axis is responsible for retention in BM of acute lymphoid leukemia and acute myeloid leukemia (AML) cells.…”

Stromal cell‐derived factor‐1α‐induced cell proliferation and its possible regulation by CD26/dipeptidyl peptidase IV in endometrial adenocarcinoma

“…15,22,23 Moreover, Murakami et al 14 reported that in a murine in vivo model, CXCR4-transfected melanoma cells demonstrated a marked increase in pulmonary metastasis compared to mock cells after i.v. and s.c. inoculation of tumor cells.…”