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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References
Brewster AM, Chavez-MacGregor M, Brown P. Epidemiology, biology, and treatment of triple-negative breast cancer in women of African ancestry. Lancet Oncol. 2014;15:e625–34.
Howlader N, Noone A, Krapcho M, Miller D, Brest A, Yu M, et al. SEER Cancer Statistics Review, 1975-2016. Bethesda, MD: National Cancer Institute; 2019.
Chang J, Chaudhuri O. Beyond proteases: basement membrane mechanics and cancer invasion. J Cell Biol. 2019;218:2456–69.
Guadamillas MC, Cerezo A, Del Pozo MA. Overcoming anoikis–pathways to anchorage-independent growth in cancer. J Cell Sci. 2011;124:3189–97.
Ma S, Fu A, Chiew GGY, Luo KQ. Hemodynamic shear stress stimulates migration and extravasation of tumor cells by elevating cellular oxidative level. Cancer Lett. 2017;388:239–48.
Oskarsson T, Batlle E, Massagué J.Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell. 2014;14:306–21.
Lambert AW, Pattabiraman DR, Weinberg RA. Emerging biological principles of metastasis. Cell. 2017;168:670–91.
Hondermarck H. Neurotrophins and their receptors in breast cancer. Cytokine Growth Factor Rev. 2012;23:357–65.
Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15:731–47.
Lagadec C, Meignan S, Adriaenssens E, Foveau B, Vanhecke E, Romon R, et al. TrkA overexpression enhances growth and metastasis of breast cancer cells. Oncogene. 2009;28:1960–70.
Contreras-Zárate MJ, Day NL, Ormond DR, Borges VF, Tobet S, Gril B, et al. Estradiol induces BDNF/TrkB signaling in triple-negative breast cancer to promote brain metastases. Oncogene. 2019;38:4685–99.
Jin W, Kim GM, Kim MS, Lim MH, Yun C, Jeong J, et al. TrkC plays an essential role in breast tumor growth and metastasis. Carcinogenesis. 2010;31:1939–47.
Boiko AD, Razorenova OV, van de Rijn M, Swetter SM, Johnson DL, Ly DP, et al. Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature. 2010;466:133–7.
Fu A, Ma S, Wei N, Tan BXX, Tan EY, Luo KQ. High expression of MnSOD promotes survival of circulating breast cancer cells and increases their resistance to doxorubicin. Oncotarget. 2016;7:50239–57.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.
Bibel M, Hoppe E, Barde YA. Biochemical and functional interactions between the neurotrophin receptors trk and p75(NTR). EMBO J. 1999;18:616–22.
Ardini E, Menichincheri M, Banfi P, Bosotti R, De Ponti C, Pulci R, et al. Entrectinib, a Pan-TRK, ROS1, and ALK inhibitor with activity in multiple molecularly defined cancer indications. Mol Cancer Ther. 2016;15:628–39.
Verdi JM, Birren SJ, Ibáñez CF, Persson H, Kaplan DR, Benedetti M, et al. p75LNGFR regulates Trk signal transduction and NGF-induced neuronal differentiation in MAH cells. Neuron. 1994;12:733–45.
Saadipour K, MacLean M, Pirkle S, Ali S, Lopez-Redondo ML, Stokes DL, et al. The transmembrane domain of the p75 neurotrophin receptor stimulates phosphorylation of the TrkB tyrosine kinase receptor. J Biol Chem. 2017;292:16594–604.
Celià-Terrassa T, Kang Y. Distinctive properties of metastasis-initiating cells. Genes Dev. 2016;30:892–908.
Luo KQ, Yu VC, Pu Y, Chang DC. Application of the fluorescence resonance energy transfer method for studying the dynamics of caspase-3 activation during UV-induced apoptosis in living hela cells. Biochem Biophys Res Commun. 2001;283:1054–60.
Wang JP, Hielscher A. Fibronectin: how its aberrant expression in tumors may improve therapeutic targeting. J Cancer. 2017;8:674–82.
Katsura A, Tamura Y, Hokari S, Harada M, Morikawa M, Sakurai T, et al. ZEB1-regulated inflammatory phenotype in breast cancer cells. Mol Oncol. 2017;11:1241–62.
Mei S, Qin Q, Wu Q, Sun H, Zheng R, Zang C, et al. Cistrome Data Browser: a data portal for ChIP-Seq and chromatin accessibility data in human and mouse. Nucleic Acids Res. 2017;45:D658–62.
Shaffer SM, Dunagin MC, Torborg SR, Torre EA, Emert B, Krepler C, et al. Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance. Nature. 2017;546:431–5.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio Cancer Genomics Portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.
Goswami CP, Nakshatri H. PROGgeneV2: enhancements on the existing database. BMC Cancer. 2014;14:970.
Lee S, Jiang X. Modeling miRNA-mRNA interactions that cause phenotypic abnormality in breast cancer patients. PLoS ONE. 2017;12:e0182666.
Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi BVSK, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017;19:649–58.
Tang Z, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47:556–60.
Koren S, Bentires-Alj M. Breast tumor heterogeneity: source of fitness, hurdle for therapy. Mol Cell. 2015;60:537–46.
Verbeke S, Meignan S, Lagadec C, Germain E, Hondermarck H, Adriaenssens E, et al. Overexpression of p75NTR increases survival of breast cancer cells through p21waf1. Cell Signal. 2010;22:1864–73.
Faulkner S, Jobling P, Rowe CW, Rodrigues Oliveira SM, Roselli S, Thorne RF, et al. Neurotrophin receptors TrkA, p75NTR, and Sortilin are increased and targetable in thyroid cancer. Am J Pathol. 2018;188:229–41.
Restivo G, Diener J, Cheng PF, Kiowski G, Bonalli M, Biedermann T, et al. The low affinity neurotrophin receptor CD271 regulates phenotype switching in melanoma. Nat Commun. 2017;8:1988.
Deng X, Xu G, He L, Xu M. p75NTR promotes survival of breast cancer resistant cells by regulating Bcl-2/Bax and MAPK pathway. Int J Clin Exp Pathol. 2017;10:11685–94.
Elsum IA, Martin C, Humbert PO. Scribble regulates an EMT polarity pathway through modulation of MAPK-ERK signaling to mediate junction formation. J Cell Sci. 2013;126:3990–9.
Chiu LY, Hsin IL, Yang TY, Sung WW, Chi JY, Chang JT, et al. The ERK-ZEB1 pathway mediates epithelial-mesenchymal transition in pemetrexed resistant lung cancer cells with suppression by vinca alkaloids. Oncogene. 2017;36:242–53.
Anand P, Fu A, Teoh SH, Luo KQ. Application of a fluorescence resonance energy transfer (FRET)-based biosensor for detection of drug-induced apoptosis in a 3D breast tumor model. Biotechnol Bioeng. 2015;112:1673–82.
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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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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DOI: https://doi.org/10.1038/s41388-021-01691-y
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