CDKN3 promoted triple-negative breast cancer by inhibiting ferroptosis through the upregulation of HSP90.

PURPOSE: The study aimed to investigate CDKN3 as a potential target for triple negative breast cancer (TNBC) and its mechanism in this type of cancer.

METHODS

After lentiviral transfection, various assays, including CCK8, clonogenic assay, flow cytometry, transwell, and scratch tests were conducted. Additionally, we examined CDKN3's impact on iron-induced cell death through various cellular markers and iron-related proteins. To assess CDKN3's impact on ferroptosis, we utilized the ferroptosis inhibitor Ferrostatin-1 and activator Erastin. To examine CDKN3's involvement in iron-induced cell death in TNBC, we repeated the previous experiment after introducing an HSP90 inhibitor. A 4T1 mammary fat pad graft tumor model was also conducted to validate the results of our in vitro cellular experiments.

RESULTS

In vitro experiments demonstrated that overexpression of CDKN3 promoted the growth, invasion, and migration of breast cancer cells. It also facilitated cell cycle progression from G0/G1 phase to S phase and suppressed apoptosis in TNBC cells. The knockdown of CDKN3 was the exact opposite. Overexpression of CDKN3 increased HSP90 expression, while CDKN3 knockdown decreased HSP90 expression. The impact of CDKN3 on the proliferation, migration, invasion, and ferroptosis of TNBC cells was associated with HSP90. The in vivo and in vitro experimental results were consistent, showing that CDKN3 overexpression promoted tumor growth and inhibited ferroptosis.

CONCLUSION

CDKN3 was an oncogene whose overexpression promoted the initiation and progression of TNBC by inhibiting HSP90-mediated ferroptosis.