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Function and biomedical implications of myoglobin in breast cancer

Subject Area Pathology
General Genetics and Functional Genome Biology
Cell Biology
Term from 2018 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 396924190
 
Final Report Year 2024

Final Report Abstract

The respiratory protein Myoglobin (MB) is strongly present in myocytes, but also ectopically expressed in epithelial cancer entities, particularly in luminal-type breast cancer. Previous studies linked increased MB expression with positive survival rates in breast cancer patients. The biological role of MB in epithelial tumors is unknown. To study this ectopic function of MB, we generated MB knockout models of three epithelial breast cancer cell lines. In vivo, we analyzed mammary cancer mouse models with and without Mb-KO and phenotyped human mammary tumor biopsies. MB expression patterns were validated by single-cell RNA-Seq data of breast cancer biopsies. In tumor spheroids, MB expression reduced central necrosis, possibly by impaired HIF-1α stability and elevated HIF-1α hydroxylation in an NO-dependent manner. MB furthermore scavenged H2O2-induced ROS in cell culture. Following murine mammary tumorigenesis in vivo, Mb proficiency decreased tissue hypoxia, even at increased tumor growth. In vitro MB deficiency was further associated with an increase in cell viability and proliferation in breast cancer cells at normoxia and enhancement of epithelial-to-mesenchymal transition under hypoxia, leading to attenuated migratory and invasive behavior. Underlining a potential tumor-suppressive role for MB in cancer cells, our studies further revealed a positive correlation between MB expression and apoptotic marker levels in human invasive mammary ductal carcinoma and associated MB protein abundance with a positive prognostic value, independently of the tumor suppressor p53 status. Inspired by metabolic shift-associated gene enrichment in MB-KO versus WT RNA-Seq studies, we investigated the impact of MB on fatty acid metabolism in breast epithelial cells and cell cultures. MB controls fatty acid turnover and homeostasis by promoting fatty acid oxidation, while reducing lipogenesis and stearyl-CoA desaturase activity. Oxygenated MB elevated indices of limited fatty acid ß-oxidation, resulting in more saturated and shorter fatty acid species. In addition, MB may act as an intracellular O2-dependent fatty acid shuttle, as it enhanced cytoplasmic fatty acid solubility under normoxia and fatty acid deposition to lipid droplets under hypoxia. To understand MB gene regulation in epithelial cells and cancer, we analyzed ENCODE RNA- Seq and ChIP-Seq data and identified active cis-regulatory histone marks at the MB gene in cells with high MB expression. In contrast, DNA methylation analysis in TCGA data showed only minor changes, suggesting that MB is preferentially regulated at the chromatin level. Single-cell RNA-Seq from breast tumors associated MB expression with the secretory luminal cell type and a mature, non-proliferating cell state. The emergent understanding of the function and regulation of MB in epithelial cells and cancer suggests novel potential roles for this respiratory protein. Expression quantification of MB in breast cancer biopsies in routine clinical diagnostics may improve tumor stratification, outcome prediction, and personalized therapy in cancer patients.

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