Abstract
CXCR4, the receptor for stromal-derived factor-1, is reportedly involved in breast carcinogenesis. However, the mechanisms through which CXCR4 contributes to breast cancer cell growth and metastases are poorly understood. In this study, we examined the putative in vitro and in vivo anti-cancer effects of the specific CXCR4 inhibitor AMD3465. Here, we report that AMD3465 triggers a reduction in breast cancer cell invasiveness in vitro, and promotes marked changes in oncogenic signaling proteins including a reduction in STAT3, JAK2, AKT, and CXCR4 phosphorylation and the reduced expression of GSK3 and cMYC. Using three breast cancer cell lines as murine syngeneic immunocompetent breast cancer models, we found that AMD3465 inhibited breast tumor formation and reduced tumor cell metastases to the lung and liver. Furthermore, treatment with AMD3465 significantly reduced the infiltration of myeloid CD11b positive cells at the aforementioned metastatic sites as well as the spleen implying this agent could regulate the formation of the tumor microenvironment and conceivably the premetastatic niche. In conclusion, our studies suggest that AMD3465 inhibits breast cancer growth and metastases by acting on tumor cells as well as immune cells that constitute the tumor microenvironment. This process appears to be regulated, at least in part, through the modulation of oncogenic signaling that includes the STAT3 pathway. Thus, CXCR4 could be a novel target for breast cancer therapy.
Highlights
IntroductionMetastases remain a major cause of disease morbidity and mortality
In breast cancer patients, metastases remain a major cause of disease morbidity and mortality
Increasing evidence shows that CXCR4 and its ligand stromal-derived factor-1 (SDF-1a, known as CXCL12) may play a critical role in the organ-selective process of tumorigenesis and metastasis including those observed in breast cancers [7,8,9]
Summary
Metastases remain a major cause of disease morbidity and mortality. Cross talk between cancer cells and their microenvironment is considered an essential event in tumorigenesis, invasion, and metastasis [1,3,4]. Increasing evidence shows that CXCR4 and its ligand stromal-derived factor-1 (SDF-1a, known as CXCL12) may play a critical role in the organ-selective process of tumorigenesis and metastasis including those observed in breast cancers [7,8,9]. CXCR4 expression in tumor cells has been described to be attendant with oncogenic events such as hypoxia [10], RET/PTC mutations [11,12], EGFR variantmediated invasion [13], and HER2 overexpression [14]
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