Neoadjuvant Chemotherapy Alters Neuropilin-1, PlGF, and SNAI1 Expression Levels and Predicts Breast Cancer Patients Response

Abstract

Circulating proteins hold a potential benefit as biomarkers for precision medicine. Previously, we showed that systemic levels of neuropilin-1 (NRP-1) and its associated molecules correlated with poor-prognosis breast cancer. To further identify the role of NRP-1 and its interacting molecules in correspondence with patients' response to neoadjuvant chemotherapy (NAC), we conducted a comparative study on blood and tissue samples collected from a cohort of locally advanced breast cancer patients, before and after neoadjuvant chemotherapy (NAC). From a panel of tested proteins and genes, we found that the levels of plasma NRP-1, placenta growth factor (PlGF) and immune cell expression of the transcription factor SNAI1 before and after NAC were significantly different. Paired t -test analysis of 22 locally advanced breast cancer patients showed that plasma NRP-1 levels were increased significantly ( p = 0.018) post-NAC in patients with pathological partial response (pPR). Kaplan–Meier analysis indicated that patients who received NAC cycles and their excised tumors remained with high levels of NRP-1 had a lower overall survival compared with patients whose tissue NRP-1 decreased post-NAC (log-rank p = 0.049). In vitro validation of the former result showed an increase in the secreted and cellular NRP-1 levels in resistant MDA-MB-231 cells to the most common NAC regimen Adriyamicin/cyclophosphamide+Paclitaxel (AC+PAC). In addition, NRP-1 knockdown in MDA-MB-231 cells sensitized the cells to AC and more profoundly to PAC treatment and the cells sensitivity was proportional to the expressed levels of NRP-1. Unlike NRP-1, circulating PlGF was significantly increased ( p = 0.014) in patients with a pathological complete response (pCR). SNAI1 expression in immune cells showed a significant increase ( p = 0.018) in patients with pCR, consistent with its posited protective role. We conclude that increased plasma and tissue NRP-1 post-NAC correlate with pPR and shorter overall survival, respectively. These observations support the need to consider anti-NRP-1 as a potential targeted therapy for breast cancer patients who are identified with high NRP-1 levels. Meanwhile, the increase in both PlGF and SNAI1 in pCR patients potentially suggests their antitumorigenic role in breast cancer that paves the way for further mechanistic investigation to validate their role as potential predictive markers for pCR in breast cancer.

The miR-124-3p/Neuropilin-1 Axis Contributes to the Proliferation and Metastasis of Triple-Negative Breast Cancer Cells and Co-Activates the TGF-β Pathway

“…It has been reported that the expression level of NRP-1 correlates with lymph metastasis (13,15) and inversely correlates with the survival in breast cancer (16). A recent study suggests that NRP-1 may be an independent prognostic factor for TNBC patients (43) and increased NRP-1 expression has been observed after neoadjuvant chemotherapy in breast cancer patients (44). All these studies highlight the significance and importance of NRP-1 in breast cancer, particularly, TNBC.…”

Long noncoding RNA RP11-70C1.3 confers chemoresistance of breast cancer cells through miR-6736-3p/NRP-1 axis

“…Our previous studies demonstrated that NRP-1 acts as an oncogene in breast cancer progression [5][6][7][8]. Furthermore, recent evidence showed a close association of NRP-1 and breast cancer chemoresistance [9][10][11]. Collectively, the above mentioned findings indicate that NRP-1 is an crucial regulator in breast cancer pathogenesis and might be responsible for the chemoresistance-medicated by RP11-70C1.3/miR-6736-3p.…”

“…Previously, we reported that NRP-1 was frequently upregulated in breast cancer and functioned as an oncogene to accelerate tumorigenesis and progression by promoting proliferation, metastasis and stemness [5][6][7][8]. Recent studies revealed that NRP-1 could promote breast cancer cells resistance to ADM and PTX resistance through activation of ITGB3/FAK/NF-kB p65 axis and downregulation of BCRP/ABCG2 [9][10][11]. However, a more detailed role of NRP-1 upregulation in breast cancer pathogenesis has not been fully elucidated.…”

Modeling Neoadjuvant chemotherapy resistance in vitro increased NRP‐1 and HER2 expression and converted MCF7 breast cancer subtype

“…The overexpression of NRP‐1 triggered the up‐regulation of EMT‐related molecules vimentin and ZEB1, which is consistent with our previous finding that NRP‐1 is positively correlated with EMT (Adham et al, ). Recently, we showed that higher NRP‐1 levels in the plasma and tissue of breast cancer patients after NAC were correlated with reduced patient response and overall survival, respectively, and NRP‐1 knockdown in MDA‐MB‐231 cells improved the sensitivity of the cells to chemotherapy (Al‐Zeheimi et al, ). Although the transporter protein BCRP/ABCG2 is a known marker of multidrug resistance (Li, Chua, Kunnath, & Chowdhury, ), its expression in resistant MDA‐MB‐231 model was decreased while NRP‐1 and the downstream survival molecules were increased, indicating that BCRP/ABCG2 does not necessarily drive NAC resistance in the context of breast cancer.…”