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

Abstract

Background and Purpose: Patients with locally advanced breast cancer usually receive third-generation neoadjuvant chemotherapy (NAC). Although NAC treatment improved the overall survival, patients' response varies, some acquire resistance and others exhibit a conversion in their breast cancer molecular subtype. We aimed to identify the molecular changes involved in NAC resistance attempting to find new therapeutic targets in different breast cancer subtypes. Experimental Approach: We modelled NAC treatments used in clinical practice and generated resistant cell lines in vitro. The resistant cells were generated by consecutive treatment with four cycles of doxorubicin (adriamycin)/cyclophosphamide (4xAC) followed by an additional four cycles of paclitaxel (4xAC + 4xPAC). Key Results: Our data revealed distinct mechanisms of resistance depending on breast cancer subtype and drugs used. MDA-MB-231 cells resistant to 4xAC + 4xPAC activated neuropilin-1/TNC/integrin β3/FAK/NF-κB p65 axis and displayed a decrease in breast cancer resistance protein (BCRP/ABCB2). However, MCF7 cells resistant to 4xAC treatments induced HER2 expression, which converted MCF7 subtype from luminal A to luminal B HER2 type, up-regulated neuropilin-1, oestrogen receptor-α, and EGFR, and activated PI3K/Akt/NF-κB p65 axis. However, MCF7 cells resistant to 4xAC + 4xPAC exhibited down-regulation of the survival axis and up-regulated BCRP/ABCG2. Co-immunoprecipitation demonstrated a novel interaction between HER2 and neuropilin-1 driving the resistance features.Conclusions and Implications: The concurrent increase in neuropilin-1 and HER2 upon resistance and the inverse relationship between neuropilin-1 and BCRP/ABCG2 suggest that, in addition to HER2, neuropilin-1 status should be assessed in patients undergoing NAC, and as a potential drug target for refractory breast cancer.

Discovery of Selective and Potent ATR Degrader for Exploration its Kinase‐Independent Functions in Acute Myeloid Leukemia Cells

“…In total, compared to the ATR inhibitor group, 56 differentially expressed genes were identified. Notably, the PI3K‐AKT signaling pathway was significantly enriched in cells treated with the ATR degrader ( FN1, LAMB1, OSMR , and TNC were downregulated according to the RNA sequencing data) [39–43] . Subsequent western blotting was performed to validate these findings.…”

“…Notably, the PI3K-AKT signaling pathway was significantly enriched in cells treated with the ATR degrader (FN1, LAMB1, OSMR, and TNC were downregulated according to the RNA sequencing data). [39][40][41][42][43] Subsequent western blotting was performed to validate these findings. A clear downregulation of p-PI3K and p-AKT levels was observed following ATR degradation (Figure 7F).…”

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 - 8 ]. Furthermore, recent evidence showed a close association of NRP-1 and breast cancer chemoresistance [ 9 - 11 ]. Collectively, the above mentioned findings indicate that NRP-1 is a 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.…”