The role of transferrin receptor in the emergence of gemcitabine resistance in breast cancer

Cancer is a multifactorial disease driven by both genetic and environmental influences, accounting for over 10 million deaths annually. Among various types, breast cancer remains one of the most prevalent and challenging to treat, particularly in its advanced stages due to the frequent development of resistance to chemotherapeutic agents. Gemcitabine (GEM), a nucleoside analog, is commonly used in treating solid tumors; however, GEM resistance in breast cancer cells significantly compromises therapeutic efficacy. Understanding the molecular basis of such resistance is essential for the advancement of effective treatment strategies. Recent studies have suggested that the transferrin receptor (TFRC), a key regulator of cellular iron uptake, may contribute to chemotherapy resistance. In this study, GEM-resistant MCF-7 breast cancer cells (MCF-7GEM-R) were generated in vitro to investigate the potential role of TFRC in GEM resistance. Following the establishment of resistance, the TFRC gene was silenced in these cells. Functional assays demonstrated a significant decrease in cell viability in TFRC-silenced MCF-7GEM-R cells compared to their non-silenced counterparts, indicating the involvement of TFRC in maintaining resistance. Furthermore, qRT-PCR analysis confirmed that TFRC expression was upregulated in GEM-resistant cells but markedly reduced following gene silencing. These findings suggest a critical role for TFRC in the development of GEM resistance in breast cancer cells. Targeting TFRC could therefore represent a novel therapeutic strategy for overcoming drug resistance. Overall, this study underscores the relevance of iron metabolism in cancer drug resistance and identifies TFRC as a potentially targetable biomarker in breast cancer therapy.