Chemotaxis mediated by chemokine receptors such as CXCR4 plays a key role in lymphocyte homing and hematopoiesis as well as in breast cancer metastasis.
The mechanism for organ-specific metastasis is poorly understood, although evidence has suggested that the chemokine stromal derived factor-1 (CXCL12) and its cognate receptor CXCR4 may regulate breast cancer metastasis.
These results suggest that T140 analogs have potential use for cancer therapy, and that small molecular CXCR4 antagonists could potentially replace neutralizing antibodies as anti-metastatic agents for breast cancer.
We further showed that inducible knockdown of endogenous CXC chemokine receptor-4 (CXCR4) gene expression in breast cancer cells resulted in significant inhibition of breast cancer cell migration in vitro.
The luciferase activities in multiple cancer cell lines infected with recombinant adenovirus reAdGL3BCXCR4 or the control vector reAdGL3BCMV revealed that the CXCR4 promoter exhibited relatively high transcriptional activity in a breast cancer cell line, MDA-MB-361, and two ovarian cancer cell lines, OVCAR-3 and SKOV3. ip1, 65% (P=0.0087), 16.7% (P=0.1) and 20% (P=0.0079) compared to that of the CMV promoter, respectively, and low expression, 4.9 and 0.1%, respectively, in both normal cell lines HFBC and HMEC.
Similar effects of CXCR4 overexpression on tumor growth in vivo were also noted in two breast cancer lines, suggesting that the observed effect of CXCR4 is not unique to prostate tumor cells.
Taken together, these studies show a novel mechanism by which CHK down-regulates CXCR4 through the YY1 transcription factor, leading to decreased CXCR4-mediated breast cancer cell motility and migration.
SDF-1, together with its receptor CXCR4 may provide important information for predicting the aggressive nature and constitute important therapeutic targets in human breast cancer.
Experimental evidence suggests that CXCR4, a Gi protein-coupled receptor for the ligand CXCL12/stromal cell-derived factor-1alpha (SDF-1alpha), plays a role in breast cancer metastasis.
Here, we report that hepatocyte growth factor and hypoxia may contribute to breast carcinoma cell invasiveness by inducing the chemokine receptorCXCR4.
Overall, the CXCR4 promoter exhibited the highest luciferase activity in breast cancer cell lines, primary breast cancer cells and breast cancer tissue slices.
We found that PMVs 1) transferred PLT-derived integrin CD41 to the surface of breast cancer cells and enhanced their adhesion to endothelial cells; 2) increased CXCR4 expression and chemotaxis toward a stromal-derived factor-1 gradient in invasive MDA-231 and BT-549 cells; 3) increased phosphorylation of the mitogen-activated protein kinase p42/44 and AKT signaling pathways; 4) stimulated the production of MMPs in invasive MDA-231 and BT-549 cells and their chemoinvasion across the reconstituted basement membrane Matrigel; and 5) induced the secretion of MMP-9 by marrow fibroblasts and stimulated the secretion of both MMP-2 and MMP-9 in cocultures of fibroblasts with MDA-MB-231 cells.
Recent studies have indicated that expression of chemokine receptors CXCR4 and CCR7 could be an indicator of the metastatic potential of breast cancer.
We therefore propose that one mechanism whereby dioxin may protect against breast cancer is via downregulation of CXCR4 and CXCL12, thereby inhibiting progression of the disease.
In this study, we evaluated the role of CXCR4 overexpression in breast cancer and determined whether it can serve as a potential marker of tumor recurrence in HER-2 negative tumors.
While CXCR4 was consistently detected, expression of CXCL12 characteristic of human mammary epithelium was silenced by promoter hypermethylation in breast cancer cell lines and primary mammary tumors.
In conclusion, we show that activation of CXCR4 transduces proliferative signals from the E2 receptor to EGFR, whose inhibition is able to revert breast cancer cell proliferation induced by multiple receptor activation.
Nuclear YB-1 expression was positively correlated with HER2 (P = 0.0153) and negatively correlated with ER alpha (P = 0.0122) and CXCR4 (P = 0.0166) in human breast cancer clinical specimens but was not correlated with EGFR expression.