title: The CXCR4 antagonist AMD3465 regulates oncogenic signaling and invasiveness in vitro and prevents breast cancer growth and metastasis in vivo.
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.
authors.affiliation: Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Ling
authors.forename: Erika
authors.initials: E
authors.lastname: Spaeth
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
authors.forename: Yuexi
authors.initials: Y
authors.lastname: Shi
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhang
authors.forename: Wendy
authors.initials: W
authors.lastname: Schober
authors.forename: Numsen
authors.initials: N
authors.lastname: Hail
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins; D006652:Histological Techniques; D008156:Luciferases; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C514936:CXCR4 protein, mouse; C503590:N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine; D011725:Pyridines; D019718:Receptors, CXCR4; D049452:Green Fluorescent Proteins; D008156:Luciferases