Abstract
BackgroundNeuropilin-1 (NRP-1), a non-tyrosine kinase glycoprotein receptor, is associated with poor prognosis breast cancer, however transcriptomic changes triggered by NRP-1 overexpression and its association with chemoresistance in breast cancer have not yet been explored.MethodsBT-474 NRP-1 variant cells were generated by stable overexpression of NRP-1 in the BT-474 breast cancer cell line. RNA sequencing and qRT-PCR were conducted to identify differentially expressed genes. The role of an upregulated oncogene, Tenascin C (TNC) and its associated pathway was investigated by siRNA-mediated knockdown. Resistant variants of the control and BT-474 NRP-1 cells were generated by sequential treatment with four cycles of Adriamycin/Cyclophosphamide (4xAC) followed by four cycles of Paclitaxel (4xAC + 4xPAC).ResultsNRP-1 overexpression increased cellular tumorigenic behavior. RNA sequencing identified upregulation of an oncogene, Tenascin-C (TNC) and downregulation of several tumor suppressors in BT-474 NRP-1 cells. Additionally, protein analysis indicated activation of the TNC-associated integrin β3 (ITGB3) pathway via focal adhesion kinase (FAK), Akt (Ser473) and nuclear factor kappa B (NF-kB) p65. siRNA-mediated TNC knockdown ablated the migratory capacity of BT-474 NRP-1 cells and inactivated FAK/Akt473 signaling. NRP-1 overexpressing cells downregulated breast cancer resistance protein (BCRP/ABCG2). Consequently, sequential treatment with Adriamycin/Cyclophosphamide (AC) cytotoxic drugs to generate resistant cells indicated that BT-474 NRP-1 cells increased sensitivity to treatment by inactivating NRP-1/ITGB3/FAK/Akt/NF-kB p65 signaling compared to wild-type BT-474 resistant cells.ConclusionsWe thus report a novel mechanism correlating high baseline NRP-1 with upregulated TNC/ITGB3 signaling, but decreased ABCG2 expression, which sensitizes BT-474 NRP-1 cells to Adriamycin/Cyclophosphamide. The study emphasizes on the targetability of the NRP-1/ITGB3 axis and its potential as a predictive biomarker for chemotherapy response.
Highlights
Neuropilin-1 (NRP-1), a non-tyrosine kinase glycoprotein receptor, is associated with poor prognosis breast cancer, transcriptomic changes triggered by NRP-1 overexpression and its association with chemoresistance in breast cancer have not yet been explored
Recombinant NRP-1 overexpression increased the tumorigenic ability of BT-474 In order to understand the functional role of NRP-1 in breast cancer progression, NRP-1 was stably overexpressed in the BT-474 cell line, which has very low baseline levels of NRP-1 compared to other breast cancer cell lines such as MDA-MB-231 and MCF-7 (Fig. 1a)
We describe a novel association between NRP-1 and Tenascin C (TNC) expression, an extracellular matrix (ECM) glycoprotein molecule that induces epithelial to mesenchymal transition (EMT), migration, proliferation and immune modulations in cancer [11, 21]
Summary
Neuropilin-1 (NRP-1), a non-tyrosine kinase glycoprotein receptor, is associated with poor prognosis breast cancer, transcriptomic changes triggered by NRP-1 overexpression and its association with chemoresistance in breast cancer have not yet been explored. Integrin αvβ was shown to control the metastatic ability of breast cancer cells to the brain in a mouse model [10]. The effect of NRP-1 overexpression on the ITGB3 signaling pathway and its role in chemoresistance in breast cancer has not yet been investigated. The role of NRP-1 in oncogenesis has been extensively investigated, in an era of advancement in omics technology there is a lack of studies dissecting the global changes elicited by NRP-1 modulation. This is of importance to identify novel pathways associated with NRP-1 function with the purpose of dual targeting in breast cancer patients to increase treatment efficiency. The main objectives of this study were to understand novel functional mechanism by which NRP-1 enhances breast cancer progression and to investigate the relationship of NRP-1 with acquired chemoresistance
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