Title |
Ecdysoneless Overexpression Drives Mammary Tumorigenesis through Upregulation of C-MYC and Glucose Metabolism
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Published in |
Molecular Cancer Research, June 2022
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DOI | 10.1158/1541-7786.mcr-22-0122 |
Pubmed ID | |
Authors |
Bhopal C. Mohapatra, Sameer Mirza, Aditya Bele, Channabasavaiah B. Gurumurthy, Mohsin Raza, Irfana Saleem, Matthew D. Storck, Aniruddha Sarkar, Sai Sundeep Kollala, Surendra K. Shukla, Siddesh Southekal, Kay-Uwe Wagner, Fang Qiu, Subodh M. Lele, Mansour A. Alsaleem, Emad A. Rakha, Chittibabu Guda, Pankaj K. Singh, Robert D. Cardiff, Hamid Band, Vimla Band |
Abstract |
Ecdysoneless (ECD) protein is essential for embryogenesis, cell cycle progression and cellular stress mitigation with an emerging role in mRNA biogenesis. We have previously shown that ECD protein as well as its mRNA are overexpressed in breast cancer (BC) and ECD overexpression predicts shorter survival in BC patients. However, the genetic evidence for an oncogenic role of ECD has not been established. Here, we generated transgenic mice with mammary epithelium-targeted overexpression of an inducible human ECD transgene (ECDTg) mouse. Significantly, ECDTg mice develop mammary hyperplasia, pre-neoplastic lesions, and heterogeneous tumors with occasional lung metastasis. ECDTg tumors exhibit epithelial to mesenchymal transition and cancer stem cells characteristics. Organoid cultures of ECDTg tumors showed ECD dependency for in vitro oncogenic phenotype and in vivo growth when implanted in mice. RNA-Seq analysis of ECDTg tumors showed a c-MYC signature, and alterations in ECD levels regulated c-MYC mRNA and protein levels as well as glucose metabolism. ECD knockdown-induced decrease in glucose uptake was rescued by overexpression of mouse ECD as well as c-MYC. Publicly available expression data analyses showed a significant correlation of ECD and c-MYC overexpression in BC, and ECD and c-MYC co-expression exhibits worse survival in BC patients. Taken together, we establish a novel role of overexpressed ECD as an oncogenesis driver in the mouse mammary gland through upregulation of c-MYC-mediated glucose metabolism. Implications: We demonstrate ECD overexpression in the mammary gland of mice led to the development of a tumor progression model through upregulation of c-MYC signaling and glucose metabolism. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 2 | 22% |
Unknown | 7 | 78% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 6 | 67% |
Scientists | 3 | 33% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 10 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 2 | 20% |
Student > Bachelor | 2 | 20% |
Student > Master | 2 | 20% |
Lecturer | 1 | 10% |
Student > Ph. D. Student | 1 | 10% |
Other | 0 | 0% |
Unknown | 2 | 20% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 8 | 80% |
Unknown | 2 | 20% |