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Epigenetic targeting of neuropilin-1 prevents bypass signaling in drug-resistant breast cancer
Journal article   Open access   Peer reviewed

Epigenetic targeting of neuropilin-1 prevents bypass signaling in drug-resistant breast cancer

Ammara Abdullah, Saeed Salehin Akhand, Juan Sebastian Paez Paez, Wells Brown, Li Pan, Sarah Libring, Michael Badamy, Emily Dykuizen, Luis Solorio, W. Andy Tao, …
Oncogene, Vol.40(2), pp.322-333
01/14/2021
DOI: 10.1038/s41388-020-01530-6
PMCID: 7808937
PMID: 33128042
url
https://doi.org/10.1038/s41388-020-01530-6View
Published (Version of record) Open Access

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Abstract

Human epidermal growth factor receptor 2 (HER2)-amplified breast cancers are treated using targeted antibodies and kinase inhibitors, but resistance to these therapies leads to systemic tumor recurrence of metastatic disease. Herein, we conducted gene expression analyses of HER2 kinase inhibitor-resistant cell lines as compared to their drug-sensitive counterparts. These data demonstrate the induction of epithelial-mesenchymal transition (EMT), which included enhanced expression of fibroblast growth factor receptor 1 (FGFR1) and axonal guidance molecules known as neuropilins (NRPs). Immunoprecipitation of FGFR1 coupled with mass spectroscopy indicated that FGFR1 forms a physical complex with NRPs, which is enhanced upon induction of EMT. Confocal imaging revealed that FGFR1 and NRP1 predominantly interact throughout the cytoplasm. Along these lines, short hairpin RNA-mediated depletion of NRP1, but not the use of NRP1-blocking antibodies, inhibited FGFR signaling and reduced tumor cell growth in vitro and in vivo. Our results further indicate that NRP1 upregulation during EMT is mediated via binding of the chromatin reader protein, bromodomain containing 4 (BRD4) in the NRP1 proximal promoter region. Pharmacological inhibition of BRD4 decreased NRP1 expression and ablated FGF-mediated tumor cell growth. Overall, our studies indicate that NRPs facilitate aberrant growth factor signaling during EMT-associated drug resistance and metastasis. Pharmacological combination of epigenetic modulators with FGFR-targeted kinase inhibitors may provide improved outcomes for breast cancer patients with drug-resistant metastatic disease.
 Apoptosis Animals Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - pathology Cell Proliferation Drug Resistance, Neoplasm - genetics Epigenesis, Genetic Epithelial-Mesenchymal Transition Female Gene Expression Regulation, Neoplastic - drug effects Humans Mice Mice, Inbred BALB C Mice, Nude Neuropilin-1 - genetics Neuropilin-1 - metabolism Protein Kinase Inhibitors - pharmacology Receptor, Fibroblast Growth Factor, Type 1 - genetics Receptor, Fibroblast Growth Factor, Type 1 - metabolism Tumor Cells, Cultured Xenograft Model Antitumor Assays

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