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: Tinghong Ye, Xiawei Wei, Tao Yin, Yong Xia, Deliang Li, Bin Shao, Xuejiao Song, Sisi He, Min Luo, Xiang Gao, Zhiyao He, Can Luo, Ying Xiong, Ningyu Wang, Jun Zeng, Lifeng Zhao, Guobo Shen, Yongmei Xie, Luoting Yu, Yuquan Wei
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 143 Issue 3 Pg. 435-46 (Feb 2014) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 24398778 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• PD 173074
• Pyrimidines
• Receptors, Fibroblast Growth Factor
• Fibroblast Growth Factors

Topics

• Animals
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Female
• Fibroblast Growth Factors (genetics, metabolism)
• Humans
• Mammary Neoplasms, Experimental (drug therapy, genetics)
• Mice
• Neoplasm Metastasis
• Pyrimidines (administration & dosage)
• Receptors, Fibroblast Growth Factor (antagonists & inhibitors, genetics)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays