Nuclear respiratory factor-1 and bioenergetics in tamoxifen-resistant breast cancer cells

Brandie N. Radde, Margarita M. Ivanova, Huy Xuan Mai, Negin Alizadeh-Rad, Kellianne Piell, Patrick Van Hoose, Marsha P. Cole, Penn Muluhngwi, Ted S. Kalbfleisch, Eric C. Rouchka, Bradford G. Hill, Carolyn M. Klinge

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Acquired tamoxifen (TAM) resistance is a significant clinical problem in treating patients with estrogen receptor α (ERα)+ breast cancer. We reported that ERα 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-1and 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. LCC1, 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.

Original languageEnglish
Pages (from-to)222-231
Number of pages10
JournalExperimental Cell Research
Volume347
Issue number1
DOIs
StatePublished - Sep 10 2016

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Inc.

Keywords

  • Breast cancer
  • Mitochondrial oxidative phosphorylation
  • NRF-1
  • Tamoxifen-resistance

ASJC Scopus subject areas

  • Cell Biology

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