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

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.

Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling

“…NRP1 forms a complex with FGFR1 in the cytoplasm, which increases during EMT in HER2 + drug-resistant breast cancer cells. This suggests a role for NRP1-mediated FGFR signaling in breast cancer progression and EMT [ 272 ].…”

Communication Between Epithelial–Mesenchymal Plasticity and Cancer Stem Cells: New Insights Into Cancer Progression

“…Epithelial-mesenchymal transition (EMT) is the process through which epithelial cells alter their phenotype, enabling them to lose their main epithelial cell traits and convert into cells expressing mesenchymal cell markers (1,2). Following the EMT, cells switch from polygonal to spindle-like fusiform shape, lose cell polarity, and gain increased resistance to apoptosis and the ability to migrate and invade (3)(4)(5)(6)(7)(8). The EMT occurs in various physiological and pathological conditions, including embryonic processes essential for normal development, tissue morphogenesis and repair, tissue reconstruction, fibrogenesis, and tumorigenesis (9)(10)(11)(12).…”

Stationed or Relocating: The Seesawing EMT/MET Determinants from Embryonic Development to Cancer Metastasis

“…For example, in breast cancer, semaphorin 3B inhibits GATA3 to reduce cell migration [ 174 ]. In HER2-related drug-resistant breast cancer cells, it was also found that an increase in neuropilin-1 can benefit cells, bypass drug inhibition, and promote cell growth in the lung [ 175 ]. In addition, these stimuli are also accompanied by the activation of ILK signaling, resulting in cell type changes that allow the cells to migrate [ 176 , 177 , 178 ].…”