Bnip3 Limits Hif-1 Alpha Stabilization And Metastasis In A Mouse Model Of Breast Cancer Through Effects On Mitochondrial Integrity And Ros Generation

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL BNIP3 is a hypoxia-inducible mitochondrial protein that has been implicated in mitochondrial fragmentation and mitophagy. BNIP3 protein is also up-regulated at pre-malignant stages of various different human cancers, including breast cancer and down-regulated later through a variety of mechanisms. To examine the role of BNip3 in tumor progression to metastasis, we crossed mice carrying a targeted deletion in the mouse BNip3 gene to the MMTV-PyMT mouse model of breast cancer. All analyses were performed with mice on a pure FVB/N genetic background. Loss of BNip3 promoted S phase entry that was associated with increased primary tumor growth. There was highly significant increase in the numbers of lung metastases and a reduced latency to metastasis in the MMTV-PyMT;BNip3-/- mice compared to control MMTV-PyMT;BNip3+/+ mice. BNip3 null tumors showed increased invasive properties and nuclear grade at earlier stages, a phenotype that was transplantable to wild-type host mice arguing that the increased invasiveness was intrinsic to BNip3 null tumor cells. BNip3 null tumor cells exhibited abnormal mitochondria, reduced mitochondrial membrane potential, increased ROS levels and increased hypoxia. Their invasive pathology was also associated with increased HIF-1α levels, increased HIF target gene expression and increased CD31-positive blood vessel formation. Quenching ROS limited Hif-1α stabilization, reduced angiogenesis and metastasis in MMTV-PyMT;BNip3-/- mouse tumors to wild-type levels. These results suggest that BNip3 is a metastasis suppressor by virtue of its role in maintaining mitochondrial integrity that mitigates against the metastasis promoting activity of reactive oxygen and hypoxia. Work on this project is supported by NIH/NCI RO1-CA131188 and by Department of Defense BRCP W81XWH-09-1-0587. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3938. doi:1538-7445.AM2012-3938