Abstract
Abstract BNIP3 is a hypoxia-inducible mitochondrial protein that has been implicated in mitochondrial fragmentation and subsequent mitophagy. BNIP3 protein has also been shown to be up-regulated at pre-malignant stages of various different human cancers, including breast cancer and down-regulated later through a variety of mechanisms, including promoter methylation and altered sub-cellular localization. With an established role for hypoxia in promoting invasiveness and progression to metastasis in breast cancer, we were interested to determine how BNIP3 (as a HIF target gene) acted in tumor progression. To do this, 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 on mice backcrossed onto a pure FVB/N genetic background. We show that while loss of BNip3 has only a modest effect on primary tumor growth, there is a highly significant increase in the numbers of lung metastases and a reduced latency to metastasis in the MMTV-PyMTl;BNip3-/- mice compared to control MMTV-PyMT;BNip3+/+ mice. BNip3 null tumors showed increased invasive properties and nuclear grade at earlier stages that were transplantable to wild-type host mice arguing that the phenotype was cell-intrinsic to BNip3 null tumor cells. This invasive pathology was also associated with increased tumor cell proliferation, increased HIF-1α levels, increased CD31-positive blood vessel formation and elevated MMPase activity. BNip3 null tumor cells exhibited abnormal mitochondria, reduced mitochondrial membrane potential and increased ROS levels. In vitro, quenching ROS limited the increased invasion/migration properties of BNip3 null tumor cells under hypoxia. 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 hypoxia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2804. doi:10.1158/1538-7445.AM2011-2804
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