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Inhibition of FGFR signaling by PD173074 improves antitumor immunity and impairs breast cancer metastasis

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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.

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Abbreviations

FGF:

Fibroblast growth factor

FGFR:

Fibroblast growth factor receptor

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide

PBS:

Phosphate-buffered saline

TUNEL:

Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end-labeling

DMSO:

Dimethyl sulfoxide

FCM:

Flow cytometry

SPF:

Specific-pathogen-free

SD:

Standard deviation

MVD:

Microvessel density

MDSCs:

Myeloid-derived suppressor cells

RTKs:

Receptor tyrosine kinases

CrEL:

Cremophor EL

i.p.:

Intraperitoneally

PVDF:

Polyvinylidene difluoride

N.S:

Normal saline

H&E:

Hematoxylin and eosin

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Acknowledgments

We gratefully acknowledge Yu-Peng Yan, Yong-Xia Zhu and Li Liu for helping in cell culturing. This study was funded by the National Key Basic Research Program of China (2010 CB 529900) and the National Natural Science Foundation of China (81123003).

Conflict of interest

The authors declared no conflicts of interest.

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Authors and Affiliations

  1. State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 17, Section 3 Renmin South Road, Chengdu, 610041, China

    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

  2. West China School of Pharmacy, Sichuan University, Chengdu, 610041, China

    Xiawei Wei

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  1. Tinghong Ye
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Correspondence to Luoting Yu or Yuquan Wei.

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Tinghong Ye and Xiawei Wei have contributed equally to this work.

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Ye, T., Wei, X., Yin, T. et al. Inhibition of FGFR signaling by PD173074 improves antitumor immunity and impairs breast cancer metastasis. Breast Cancer Res Treat 143, 435–446 (2014). https://doi.org/10.1007/s10549-013-2829-y

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