Drug resistance and the recurrence of breast cancer remain significant challenges for oncologists. Patients with locally advanced breast cancer undergo neoadjuvant chemotherapy (NAC). Despite the proven improvement in overall survival with NAC treatment, there is considerable variability in patients' responses. This study aimed to pinpoint the molecular alterations associated with NAC resistance to uncover novel therapeutic targets across two breast cancer subtypes. Our findings revealed distinct resistance mechanisms based on the breast cancer subtype and specific drugs utilized. The triple negative MDA-MB-231 cells resistant to Adriamycin/cyclophosphamide and Paclitaxel activated the NRP-1/TNC/Integrin β3/FAK/NF-κBp65 axis. Conversely, the luminal A MCF7 cells resistant to Adriamycin/cyclophosphamide (4xAC) exhibited increased HER-2 expression, resulting in a subtype conversion from luminal A to luminal B-HER-2 type. Resistant MCF-7 cells upregulated NRP-1, ER-α, and EGFR and activated the PI3K/Akt/NF-κBp65 survival axis. Co-immunoprecipitation revealed a novel interaction between HER-2 and NRP-1, driving the observed resistance characteristics. The findings highlighted differential mechanisms of resistance between the two cell lines. NAC prompted resistance in MCF7 cancer cells by elevating HER-2 and NRP-1 levels, with observed evidence of their interaction. Our results emphasized the significant involvement of NRP-1 upregulation in resistance to NAC in MDA-M-MB-231 and MCF-7 cells representing the triple-negative and luminal subtypes.

Dr. Noura Al-Zeheimi is a distinguished academic and researcher currently serving as a visiting faculty member at Sultan Qaboos University's Department of Biology. She earned her PhD in Biology from the same institution in 2019, specializing in breast cancer research. Dr Al-Zeheimi's passion for advancing scientific knowledge led her to continue her research journey as a postdoctoral fellow in the cancer biology laboratory at Sultan Qaboos University. In 2019, she was honoured with the National Research Award in the Health and Social Services Sector, Category I (PhD holders), recognizing her outstanding achievements in her field.