title: The chemokine receptor CCR4 promotes tumor growth and lung metastasis in breast cancer.
abstract: Increasing evidence has shown that chemokines and chemokine receptors are associated with tumor growth and metastasis. CCR4, an important chemokine receptor for regulating immune homeostasis, is thought to be involved in hematologic malignancies and has also recently implicated in some solid tumors, such as gastric cancer. The possible role of CCR4 in breast cancer has not been well elucidated. In this study, we show that CCR4 is differentially expressed in human breast cancer cell lines. Specifically, we find that CCR4 is overexpressed in breast cancer cell lines with high metastatic potential. More importantly, we used a combination of overexpression and RNA interference to demonstrate that CCR4 promotes breast tumor growth and lung metastasis in mice. Furthermore, we find that microvessel density is significantly increased in tumors formed by CCR4-overexpressing cells and decreased in those formed by CCR4-knockdown cells. We find that overexpression of CCR4 can enhance the chemotactic response of breast cancer cells to CCL17. However, the expression of CCR4 does not affect the proliferation of breast cancer cells in vitro. Furthermore, we show that CCR4 expression is positively correlated with HER2 expression, tumor recurrence and lymph node, lung and bone metastasis (P < 0.05). Multivariate analysis showed that CCR4 expression is a significant independent prognostic factor for overall survival (P = 0.036) but not for disease-free survival in patients with breast cancer (P = 0.071). Survival analysis indicated a strong association between CCR4 expression and lower overall survival (P = 0.0001) and disease-free survival (P = 0.016) in breast cancer.
authors.affiliation: Breast Cancer Institute, Cancer Hospital, Department of Oncology, Shanghai Medical College, Institutes of Biomedical Science, Fudan University, Shanghai, 200032, China.
authors.forename: Ji-Yu
authors.initials: JY
authors.lastname: Li
authors.forename: Zhou-Luo
authors.initials: ZL
authors.lastname: Ou
authors.forename: San-Jian
authors.initials: SJ
authors.lastname: Yu
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Gu
authors.forename: Chen
authors.initials: C
authors.lastname: Yang
authors.forename: Ao-Xiang
authors.initials: AX
authors.lastname: Chen
authors.forename: Gen-Hong
authors.initials: GH
authors.lastname: Di
authors.forename: Zhen-Zhou
authors.initials: ZZ
authors.lastname: Shen
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Shao
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054414:Chemokine CCL17 / Q000378:metabolism; D054422:Chemokine CCL22 / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics* / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D011379:Prognosis; D034622:RNA Interference; D054398:Receptors, CCR4 / Q000235:genetics*; D016019:Survival Analysis; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D054414:Chemokine CCL17; D054422:Chemokine CCL22; D054398:Receptors, CCR4