Abstract
The optical redox ratio (fluorescence intensity of NADH divided by that of FAD), was acquired for a panel of breast cancer cell lines to investigate how overexpression of human epidermal growth factor receptor 2 (HER2) affects tumor cell metabolism, and how tumor metabolism may be altered in response to clinically used HER2-targeted therapies. Confocal fluorescence microscopy was used to acquire NADH and FAD auto-fluorescent images. The optical redox ratio was highest in cells overexpressing HER2 and lowest in triple negative breast cancer (TNBC) cells, which lack HER2, progesterone receptor, and estrogen receptor (ER). The redox ratio in ER-positive/HER2-negative cells was higher than what was seen in TNBC cells, but lower than that in HER2 overexpressing cells. Importantly, inhibition of HER2 using trastuzumab significantly reduced the redox ratio in HER2 overexpressing cells. Furthermore, the combinatorial inhibition of HER2 and ER decreased the redox ratio in ER+/HER2+ breast cancer cells to a greater extent than inhibition of either receptor alone. Interestingly, trastuzumab had little impact upon the redox ratio in a cell line selected for acquired resistance to trastuzumab. Taken together, these data indicate that the optical redox ratio measures changes in tumor metabolism that reflect the oncogenic effects of HER2 activity within the cell, as well as the response of the cell to therapeutic inhibition of HER2. Therefore, optical redox imaging holds the promise of measuring response and resistance to receptor-targeted breast cancer therapies in real time, which could potentially impact clinical decisions and improve patient outcome.
Highlights
The course of breast cancer treatment increasingly relies on the molecular phenotype of the tumor
We and others have shown that this characteristic of cancer cells can be monitored in situ using optical imaging to measure the redox ratio, or the ratio of glycolysis to oxidative metabolism
We show that “driver” oncogenes in breast cancer cells drive aerobic glycolysis in these cells
Summary
The course of breast cancer treatment increasingly relies on the molecular phenotype of the tumor. Breast cancers that overexpress the estrogen receptor (ER) are often treated with ER-antagonists (e.g., tamoxifen, fulvestrant), while those that overexpress human epidermal growth factor receptor 2 (HER2) are often treated with HER2-inhibitors (e.g., trastuzumab, lapatinib). Treatment with trastuzumab (a monoclonal antibody which binds HER2) and lapatinib (a dual tyrosine kinase inhibitor that binds both HER2 and the epidermal growth factor receptor) has been shown to prolong survival in patients with HER2 overexpressing breast cancers [2,3,4]. Due to the importance of choosing the correct treatment for breast cancer patients, breast tumors are routinely screened for expression of ER and HER2. ER and HER2 expression are determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH)
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