Journal
EXPERIMENTAL CELL RESEARCH
Volume 347, Issue 1, Pages 222-231Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2016.08.006
Keywords
Breast cancer; NRF-1; Mitochondrial oxidative phosphorylation; Tamoxifen-resistance
Categories
Funding
- National Institutes of Health [R01 DK053220, T35 DK072923]
- University of Louisville School of Medicine
- Office of the Executive Vice President for Research and Innovation of the University of Louisville
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Acquired tamoxifen (TAM) resistance is a significant clinical problem in treating patients with estrogen receptor alpha (ER alpha)+ breast cancer. We reported that ERa increases nuclear respiratory factor-1 (NRF-1), which regulates nuclear-encoded mitochondrial gene transcription, in MCF-7 breast cancer cells and NRF-1 knockdown stimulates apoptosis. Whether NRF-1 and target gene expression is altered in endocrine resistant breast cancer cells is unknown. We measured NRF-1 and metabolic features in a cell model of progressive TAM-resistance. NRF-1 and its target mitochondrial transcription factor A (TFAM) were higher in TAM-resistant LCC2 and LCC9 cells than TAM-sensitive MCF-7 cells. Using extracellular flux assays we observed that LCC1, LCC2, and LCC9 cells showed similar oxygen consumption rate (OCR), but lower mitochondrial reserve capacity which was correlated with lower Succinate Dehydrogenase Complex, Subunit B in LCC1 and LCC2 cells. Complex III activity was lower in LCC9 than MCF-7 cells. LCCI, LCC2, and LCC9 cells had higher basal extracellular acidification (ECAR), indicating higher aerobic glycolysis, relative to MCF-7 cells. Mitochondrial bioenergetic responses to estradiol and 4-hydroxytamoxifen were reduced in the endocrine-resistant cells compared to MCF-7 cells. These results suggest the acquisition of altered metabolic phenotypes in response to long term antiestrogen treatment may increase vulnerability to metabolic stress. (C) 2016 Elsevier Inc. All rights reserved.
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