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Mitophagy is induced in response to physiological stresses, including hypoxia, as an adaptive response that decreases mitochondrial mass to promote efficient use of limiting nutrients. BNIP3L/NIX is a mitophagy cargo receptor that integrates into the outer mitochondrial membrane where it interacts with processed LC3 at growing phagophore membranes to promote mitophagy. Our preliminary data shows that elevated BNIP3L/NIX expression in basal-like breast cancers correlates with worse overall patient survival. However, the functional significance of BNIP3L/NIX for growth and progression of breast cancer has not been determined. We generated a CRISPR/Cas9 KO BNIP3L/NIX 4T1 mouse mammary tumor model to determine how loss of BNIP3L/NIX affected tumor progression and metastasis. We observed that loss of BNIP3L/NIX decreased tumor cell growth and importantly attenuated metastasis to the lungs. By performing RNA-seq analysis, we found that these striking findings were associated with a decrease in molecular signatures expression of hypoxia-inducible genes and epithelial-mesenchymal transition (EMT) genes, including Twist and Vimentin. In addition, expression of Vimentin was complete ablated in 4T1 KO BNIP3L/NIX tumors in vivo and 4T1 KO BNIP3L/NIX tumor cells had significantly reduced ability to migrate and invade in vitro. Furthermore, CRISPR/Cas9-mediated deletion of HIF1α a in the 4T1 cell model reduced Vimentin expression in a manner dependent on BNIP3L/NIX expression. These results indicate that BNIP3L/NIX acts as an oncogene downstream of HIF1α in breast cancer by promoting expression of key EMT genes, stimulating tumor cell proliferation and migration, and that targeting BNIP3L/NIX might prove an effective strategy in the clinic. Citation Format: Damian E. Berardi, Kay F. Macleod. BNIP3L/NIX promotes breast cancer growth and metastasis by inducing epithelial-mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 951. |
