Functions of BNIP3 in mammary tumorigenesis

Tumor hypoxia is associated with poor prognosis in cancer patients, and the hypoxic response promotes tumor progression in a number of ways, although direct mechanisms of metastasis promotion by hypoxia are not well understood. Hypoxia promotes the selection of tumor cells resistant to drug and stress induced death and promotes the switch to glycolytic metabolism, which allows cells to better withstand fluctuating oxygen levels common in tumors. Hypoxia also promotes angiogenesis, which is crucial for tumor growth. Furthermore, hypoxia, and the increased reactive oxygen species (ROS) that come with it, can promote proliferation, DNA damage, and epithelial to mesenchymal transition, all of which promote tumor progression.;The hypoxia-inducible protein BNIP3 has been implicated in the maintenance of mitochondrial integrity during hypoxia through regulation of mitophagy, the specific degradation of mitochondria by autophagy. BNIP3 has also been shown to be silenced in a number of human tumor types during progression to invasiveness. While the maintenance of mitochondrial integrity is important for limiting ROS and DNA damage, and dysfunctional mitochondria have been associated with tumor promotion, a direct link between mitophagy and tumorigenesis has not been made. In order to better understand the role of mitochondrial integrity and the hypoxic response in tumorigenesis, I have examined the function of BNIP3 in tumor cells and in a mouse model of mammary tumorigenesis.;While multiple reports claim that BNIP3 is a cell death inducer, I have shown that BNIP3 is required for hypoxia-induced autophagy and is not sufficient to kill cells. Furthermore, I have shown that deletion of BNIP3 in the MMTV-PyMT model of mammary tumorigenesis promotes tumor progression and metastasis. Loss of BNIP3 expression in MMTV-PyMT tumor cells leads to mitochondrial dysfunction and increased ROS, which appears to underlie the faster tumor progression and increased metastasis in BNip3-/-;MMTV-PyMT mice. I have also identified a nuclear export signal in the transmembrane domain of BNIP3 and shown that BNIP3 can be sequestered in the nucleus in human tumor cells. This result, combined with the identification of BNip3 as a tumor suppressor in mouse mammary cancer, suggests a mechanism by which the sequestration of BNIP3 in the nucleus of tumor cells could inactivate BNIP3 function, leading to increased tumor progression and metastasis.