Optical Imaging of Glucose Uptake and Mitochondrial Membrane Potential to Characterize Her2 Breast Tumor Metabolic Phenotypes.

Abstract

With the large number of women diagnosed and treated for breast cancer each year, the importance of studying recurrence has become evident due to most deaths from breast cancer resulting from tumor recurrence following therapy. To mitigate this, cellular and molecular pathways used by residual disease prior to recurrence must be studied. An altered metabolism has long been considered a hallmark of cancer, and several recent studies have gone further to report metabolic dysfunction and alterations as key to understanding the underlying behavior of dormant and recurrent cancer cells. Our group has used two probes, 2-[N-(7-nitrobenz-2-oxa-1, 3-diaxol-4-yl) amino]-2-deoxyglucose (2-NBDG) and tetramethyl rhodamine ethyl ester (TMRE), to image glucose uptake and mitochondrial membrane potential, respectively, to report changes in metabolism between primary tumors, regression, residual disease, and after regrowth in genetically engineered mouse (GEM)-derived mammospheres. Imaging revealed unique metabolic phenotypes across the stages of tumor development. Although primary mammospheres overexpressing Her2 maintained increased glucose uptake ("Warburg effect"), after Her2 downregulation, during regression and residual disease, mammospheres appeared to switch to oxidative phosphorylation. Interestingly, in mammospheres where Her2 overexpression was turned back on to model recurrence, glucose uptake was lowest, indicating a potential change in substrate preference following the reactivation of Her2, reeliciting growth. Our findings highlight the importance of imaging metabolic adaptions to gain insight into the fundamental behaviors of residual and recurrent disease. IMPLICATIONS: This study demonstrates these functional fluorescent probes' ability to report metabolic adaptations during primary tumor growth, regression, residual disease, and regrowth in Her2 breast tumors.

• Authors: Megan C Madonna, Douglas B Fox, Brian T Crouch, Jihong Lee, Caigang Zhu, Amy F Martinez, James V Alvarez, Nirmala Ramanujam
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 17 Issue 7 Pg. 1545-1555 (07 2019) ISSN: 1557-3125 [Electronic] United States
• PMID: 30902832 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Organometallic Compounds
• tetramethyl rhodamine ethyl ester
• Deoxyglucose
• Erbb2 protein, mouse
• Receptor, ErbB-2
• 4-Chloro-7-nitrobenzofurazan
• Glucose
• 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose

Topics

• 4-Chloro-7-nitrobenzofurazan (analogs & derivatives, pharmacology)
• Animals
• Animals, Genetically Modified
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Deoxyglucose (analogs & derivatives, pharmacology)
• Female
• Gene Expression Regulation, Neoplastic
• Glucose (genetics, metabolism)
• Humans
• Mammary Glands, Animal (metabolism, pathology)
• Membrane Potential, Mitochondrial (drug effects)
• Neoplasm Recurrence, Local (genetics, metabolism)
• Organometallic Compounds (pharmacology)
• Phenotype
• Receptor, ErbB-2 (genetics)