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Nerve growth factor receptor increases the tumor growth and metastatic potential of triple-negative breast cancer cells

Abstract

Cellular heterogeneity and the lack of metastatic biomarkers limit the diagnosis of and development of therapies for metastatic triple-negative breast cancer (TNBC). Thus, development of new clinically relevant markers is urgently needed. By using RNA-seq analysis, we found that nerve growth factor receptor (NGFR) was highly expressed in metastatic lung clones of MDA-MB-231 cells. This high level of NGFR expression was necessary for TNBC cells to grow into tumor spheres under nonadhesive conditions, resist anoikis, promote primary tumor growth and increase metastasis in mice. NGFR was also expressed at a high level in a greater number of TNBC patients (45%) than non-TNBC patients (23%), enriched in higher grade tumors, and negatively correlated with the overall survival of TNBC patients. Mechanistic analysis indicated that NGFR exerted its prometastatic effects by binding with neurotrophic receptor tyrosine kinase 3 (TrkC) mainly through a ligand-independent manner, which activated the MEK–ERK1–ZEB1 and PI3K–AKT signaling pathways, increased the level of fibronectin, and decreased the expression of PUMA. Notably, we observed that NGFR expression in TrkC-positive metastatic clones reduced cellular sensitivity to anti-Trk therapy. Moreover, WNT family member 5a (WNT5A) and TrkC activated NGFR transcription in a ZEB1-dependent manner. Taken together, this study identified NGFR as a novel driver for transforming TNBC into higher grade metastatic tumors. Our findings provide the basis for the future development of NGFR as a diagnostic and prognostic marker for determining the metastatic potential of TNBC and as a therapeutic target for treating TNBC patients.

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Fig. 1: Identification of NGFR and other highly expressed genes in a TNBC lung metastatic clone.
Fig. 2: NGFR is important for lung colony-formation of TNBC cells.
Fig. 3: NGFR activated TrkC in metastatic M1A cells.
Fig. 4: NGFR and TrkC synergistically contribute to sphere growth and lung colony-formation.
Fig. 5: NGFR and TrkC promoted the primary tumor growth and metastasis in an orthotopic mouse model.
Fig. 6: NGFR-Trk activated ERK and AKT signaling pathways to resist anoikis and support sphere growth.
Fig. 7: WNT5A and TrkC regulated NGFR transcription through ZEB1.
Fig. 8: Clinical relevance of NGFR expression in TNBC patients.

Data availability

All the data needed to evaluate the conclusions made in the paper are presented in the paper. Additional data related to this paper may be requested from the authors.

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Acknowledgements

We thank Dr Hao Jia from KQL’s group for his valuable suggestion and comments.

Funding

This project was funded by The Science and Technology Development Fund (FDCT), Macao SAR, China (File no. 083/2016/A2 and 068/2017/A2).

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RW and KQL designed the research studies. RW, KL, and MY conducted the experiments. RW and KQL analyzed the data. RW and KQL wrote the manuscript.

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Correspondence to Kathy Qian Luo.

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The authors declare no competing interests.

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The animal experimental protocols (UMARE-025-2017 and UMARE-026-2017) were approved by the Panel of Animal Research Ethics at the University of Macau.

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Wu, R., Li, K., Yuan, M. et al. Nerve growth factor receptor increases the tumor growth and metastatic potential of triple-negative breast cancer cells. Oncogene 40, 2165–2181 (2021). https://doi.org/10.1038/s41388-021-01691-y

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