title: Inhibition of FGFR signaling by PD173074 improves antitumor immunity and impairs breast cancer metastasis.
abstract: Aberrant fibroblast growth factor (FGF) and FGF receptor (FGFR) system have been associated with breast cancer. The objectives of our study were to investigate the effects and mechanisms of FGFR inhibition on tumor growth and metastasis on breast cancer. Our studies showed that the FGFR inhibitor PD173074 decreased the viability of several human breast cancer cells, as well as 4T1 murine mammary tumor cells. Therefore, we chose 4T1 cells to study PD173074's antitumor mechanism. Flow cytometry showed that PD173074 induced 4T1 cell apoptosis in a concentration-dependent manner. Western blot demonstrated that PD173074-induced apoptosis was correlated with the inhibition of Mcl-1 and survivin. Moreover, PD173074 also significantly increased the ratio of Bax/Bcl-2. PD173074 could also block 4T1 cell migration and invasion in vitro. In 4T1 tumor-bearing mice, PD173074 significantly inhibited tumor growth without obvious side effects. Meanwhile, PD173074 functionally reduced microvessel density and proliferation index and induced tumor apoptosis. Importantly, we found that FGFR inhibition by PD173074 reduced myeloid-derived suppressor cells (MDSCs) in the blood, spleens and tumors, accompanied by the increased infiltration of CD4(+) and CD8(+) T cells in the spleens and tumors. Furthermore, PD173074 significantly inhibited breast tumor metastasis to the lung of inoculated 4T1 breast cancer cells, which was accompanied by a reduction in MDSCs. Our findings suggested that FGFR inhibition could delay breast tumor progression, impair lung metastasis and break immunosuppression by effecting on tumor microenvironment, which may provide a promising therapeutic approach for breast cancer patient.
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 17, Section 3 Renmin South Road, Chengdu, 610041, China.
authors.forename: Tinghong
authors.initials: T
authors.lastname: Ye
authors.forename: Xiawei
authors.initials: X
authors.lastname: Wei
authors.forename: Tao
authors.initials: T
authors.lastname: Yin
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.forename: Deliang
authors.initials: D
authors.lastname: Li
authors.forename: Bin
authors.initials: B
authors.lastname: Shao
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Song
authors.forename: Sisi
authors.initials: S
authors.lastname: He
authors.forename: Min
authors.initials: M
authors.lastname: Luo
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Zhiyao
authors.initials: Z
authors.lastname: He
authors.forename: Can
authors.initials: C
authors.lastname: Luo
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.forename: Ningyu
authors.initials: N
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Zeng
authors.forename: Lifeng
authors.initials: L
authors.lastname: Zhao
authors.forename: Guobo
authors.initials: G
authors.lastname: Shen
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Xie
authors.forename: Luoting
authors.initials: L
authors.lastname: Yu
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D009362:Neoplasm Metastasis; D011743:Pyrimidines / Q000008:administration & dosage*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C115711:PD 173074; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors