Master of Science (MS)
Molecular Genetics & Cell Biology
The Ecdysoneless (ECD) protein is highly evolutionarily conserved and ubiquitously expressed across human tissues. ECD has established roles in cell cycle regulation, embryogenesis, cell survival, and RNA biogenesis. ECD mRNA and protein are overexpressed in breast cancer, and its overexpression correlates with poor patient survival, especially in ErbB2/HER2-positive breast cancer. This thesis work investigates the co-oncogenic role of ECD in ErbB2-driven oncogenesis using immortalized mammary epithelial cells. Here, we show that ECD and ErbB2 overexpression in immortalized human mammary epithelial cells increases cancer traits, such as invasion, migration, and anchorage independent growth. Significantly, ECD+ErbB2 co-overexpression further enhanced all oncogenic traits. Although mechanistically unclear, ECD overexpression resulted in increased levels of surface ErbB2 under growth factor deprivation conditions, this may have contributed to co-oncogenic function. As both ErbB2 and ECD are known to play a role in glucose metabolism, we assessed if the combination of two proteins led to a significant increase in glucose uptake. As expected, ECD or ErbB2 overexpression increased glucose uptake, however, co-overexpression did not have a significant further increase in glucose uptake under normal culture conditions. However, culturing cells in growth factor-deprived medium resulted in a significant increase in glucose uptake when both genes were co-expressed, suggesting a role of altered microenvironment in ECD+ErbB2-overexpressing tumors. Lastly, mRNA levels of several key glycolytic enzymes are increased upon ECD and ErbB2 co-overexpression, such as ENO1, PDK1, HKII, and LDHA Taken together, our findings support a co-oncogenic role of ECD in ErbB2-driven oncogenesis, which is consistent with ErbB2-positive patients with ECD overexpression exhibiting poor prognosis and short patient survival. Future studies will assess this co-oncogenic function in vivo, as well as define the mechanism of co-oncogenesis between these two genes.
Kennedy, Benjamin B., "The Co-Oncogenic Function of Ecdysoneless Protein with ErbB2 in Mammary Epithelial Cells" (2023). Theses & Dissertations. 771.
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