Breast cancer (BC) is the most common cancer for women worldwide, accounting for around 31% of all cancers affecting women (Siegel et al., 2023). Roughly one in eight women will encounter a diagnosis of BC during their life (Sung et al., 2021). Despite surgery, radiotherapy, chemotherapy, and targeted therapies come as source of solace for BC patients, their prognoses are far from ideal (Gradishar et al., 2022, Waks and Winer, 2019). There is an immediate call for more efficient therapeutic strategies against this disease.
Ferroptosis, an iron-dependent cell death process resulting from the accumulation of lipid reactive oxygen species (ROS), was conceptualized by Scott et al. in 2012 (Dixon et al., 2012). This process sets itself apart from apoptosis, autophagy, and necrosis by presenting distinctive morphological changes (Li et al., 2020). A strong link between ferroptosis and the emergence of various diseases has been validated. Specifically, ferroptosis has been observed to curb the growth of tumors in gastric, pancreatic, and BCs, and its induction can hasten the deterioration in neurodegenerative conditions (Dixon et al., 2012, Stockwell and Jiang, 2019). The potential of ferroptosis in the suppression of tumor malignancy is progressively unveiled. Drugs like Erastin, RSL3, and Deferoxamine, which are approved by the Food and Drug Administration, have been recognized for their ability to induce ferroptosis in various cancers, serving as novel anti-cancer agents (Dixon et al., 2012). Emerging evidence unveils that ferroptosis plays a significant role in BC. For example, glutathione peroxidase 4 (GPX4), an enzyme pivotal in counteracting ferroptosis, is enhanced by the methyltransferase-like protein 16 through the methylation of N6-methyladenosine (m6A), an epigenetic modification that inhibits ferroptosis and accelerates the progression of BC (Ye et al., 2023). Research by Blanchette-Farra et al. has shown that fibroblasts can elevate the synthesis of hepcidin in BC cells via the secretion of interleukin-6, which increases iron accumulation and further promotes ferroptosis in these cells (Blanchette-Farra et al., 2018). Moreover, a string of recent studies has underscored the pivotal role of mitophagy in the induction of ferroptosis (Yuan et al., 2023, Hsieh et al., 2021). A study on melanoma cells found that the inhibition of complex I (CI) of the mitochondrial respiratory chain leads to an upsurge in ROS that is dependent on mitophagy, resulting in the necroptosis and ferroptosis of melanoma cells (Basit et al., 2017). These findings support the idea that targeting mitophagy or ferroptosis could be a promising anti-cancer strategy. However, few people dabble in that field in the context of BC.
The gene encoding Fms-like tyrosine kinase 3 (FLT3) is situated at the 13q12.2 region on chromosome 13 and is part of the III-type receptor tyrosine kinases (Griffiths et al., 2005). It is believed that the extracellular portion of FLT3 houses a domain with a strong affinity for FLT3 ligand (FL), a molecule that is widely expressed across various tissues, being most abundant in peripheral blood mononuclear cells (Takahashi, 2011). The interaction between FL and FLT3 results in receptor dimerization and structural modification, cascading into the phosphorylation of downstream proteins and the subsequent activation of signaling pathways that govern cell growth, differentiation, and viability (Nitika et al., 2022). The bulk of FLT3-related research is concentrated on its implications in acute myeloid leukemia (AML), with the molecule being recognized as a promising target for AML treatment (Kiyoi et al., 2020). In the context of AML, as documented, FLT3 can also inhibit ferroptosis (Sabatier et al., 2023). Newer findings point to FLT3 being among the biomarkers linked to ferroptosis that are indicative of BC prognosis (Wu et al., 2021). Despite these insights, the exact mechanisms through which FLT3 regulates ferroptosis in BC cells have yet to be fully elucidated.
In our investigation, we have provided evidence that FLT3 is instrumental in preventing ferroptosis in BC cells. Furthermore, we have uncovered that FLT3 was regulated upstream by transcription factor AP-2 gamma (TFAP2C). TFAP2C initiated the transcriptional activation of FLT3, which then facilitated the process of mitophagy to suppress ferroptosis in BC cells. Our findings elucidated the underlying mechanism of FLT3 in inhibiting ferroptosis, which is significant for devising more specific and targeted treatment plans and for both theoretical and clinical BC management.
