TFCP2L1 suppresses breast cancer progression by promoting ferroptosis through direct and PI3K/AKT-mediated inhibition of GPX4.

Breast cancer is the most prevalent type of malignant tumor among women. Here, we identified transcription factor CP2-like 1 (TFCP2L1) as a suppressor of breast cancer cells. Patients with breast cancer have poorer prognoses when TFCP2L1 is expressed at low levels. Consistently, the expression of TFCP2L1 is greater in normal breast tissues and cells than in breast cancer tissues and cell lines. Gain- and loss-of-function experiments and xenograft tumor assays revealed that overexpression of TFCP2L1 significantly inhibited the proliferation and migration of breast cancer cells. Conversely, the knockdown of TFCP2L1 promoted the growth and migration of breast cancer cells. Mechanistically, TFCP2L1 suppresses breast cancer progression by inhibiting the expression of glutathione peroxidase 4 (GPX4), a key positive regulator of ferroptosis. Therefore, the addition of a ferroptosis inhibitor, Ferrostatin-1, can mediate the function of TFCP2L1 in breast cancer cells. On the other hand, high-throughput transcriptome sequencing revealed that TFCP2L1 negatively regulates the activity of the PI3K/AKT signaling pathway. The administration of SC79, an AKT activator, partially reversed the negative effects of TFCP2L1 on GPX4 transcription. Together, these findings indicate that TFCP2L1 functions partially by directly and indirectly regulating GPX4-mediated ferroptosis and may serve as a potential therapeutic target for breast cancer.