Function and biomedical implications of myoglobin in breast cancer

• Applicants: Professor Dr. Thomas Hankeln; Professor Dr. Glen Kristiansen
• Subject Area: Pathology ; General Genetics and Functional Genome Biology ; Cell Biology
• Term: from 2018 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 396924190

Myoglobin, known as an O2-binding respiratory protein in skeletal and cardiac myocytes, has also been detected in the past 10 years in various tumor entities, mostly of epithelial origin. For example, the globin expression is significantly correlated to increased overall survival rates in luminal breast cancers, suggesting a tumor-suppressive role of MB. We already reported that MB transcription in cancer cells is maintained by an alternative gene regulatory machinery, which is not used in myocytes. The physiological role of MB in tumors, however, remains ambiguous. Our preliminary work suggests that the globin does not exert its classic function in cellular O2-supply within tumor cells. Instead, we were able to show by comprehensive RNA-Seq analyses and verifying Western Blot experiments that the cellular response of an RNAi-mediated MB-knockdown severely impacts the differential expression of target genes of the master transcription factors HIF1a und p53. Our fundamental working model implies that MB modulates the activity of both transcription factors via its enzymatic functions in producing NO under hypoxia or scavenging NO under normoxia, functions which have already been described for MB e.g. in the context of smooth muscles. NO molecules, and possibly also MB-produced ROS, were previously reported to significantly induce the activity of wildtype p53, mutated p53 and HIF1a. Our preliminary data further imply that the presence/absence of MB also impacts the cancer cell phenotype, e.g. resulting in altered amounts of apoptotic cells and migration/invasion capacities. The globin thus appears to play a key role in tumor cell metabolism. Interestingly, the observed effects however differ with regard to the p53 genotype of the cell.In this project proposal, we intend to study the role of MB in cancer cells, as based on our working hypotheses. At different physiological O2 and NO conditions and with respect to different p53 genotypes, we will first validate the activity of PHD2/HIF1a and p53 in the presence or absence of MB in breast cancer cells. We will further examine the expression of the transcription factors target genes and resulting adaptions in cellular metabolism, cell-cycle progression and cell migration capacities. MB-dependent protein interactions and cellular cascades described in cell models will then be investigated in vivo in mouse breast tumor models who are either MB-expressing or feature an MB-knockout genotype. We further plan to continue studying the expression correlations between MB, p53 and HIF1a target genes in human breast cancer biopsies with respect to their p53-genotype and additional clinicopathological parameters.Our project promises gaining fundamental knowledge on the tumor-suppressing role of MB in cancer cells. Furthermore, the achieved understanding of the role of MB in cancer cells will potentially pave the way for developing novel diagnostic and therapeutic approaches.

• DFG Programme: Research Grants