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  3. Mitochondrial estrogen receptors alter mitochondrial priming and response to endocrine therapy in breast cancer cells

Mitochondrial estrogen receptors alter mitochondrial priming and response to endocrine therapy in breast cancer cells

  • Cell Death Discov. 2021 Jul 22;7(1):189. doi: 10.1038/s41420-021-00573-2.
Bahriye Karakas 1,  Yeliz Aka 2,  Asli Giray 3,  Sehime Gulsun Temel 4 5 6,  Ufuk Acikbas 2,  Huveyda Basaga 1,  Ozgur Gul 7,  Ozgur Kutuk 8
Affiliations

Affiliations

  • 1 Sabanci University, Molecular Biology, Genetics and Bioengineering Program, Istanbul, Turkey.
  • 2 Baskent University School of Medicine, Dept. of Immunology, Adana Dr. Turgut Noyan Medical and Research Center, Adana, Turkey.
  • 3 Department of Genetics and Bioengineering, Alanya Alaaddin Keykubat University, Alanya, Turkey.
  • 4 Bursa Uludag University, Faculty of Medicine, Department of Histology and Embryology, Bursa, Turkey.
  • 5 Bursa Uludag University, Faculty of Medicine, Department of Medical Genetics, Bursa, Turkey.
  • 6 Bursa Uludag University, Institute of Health Sciences, Department of Translational Medicine, Bursa, Turkey.
  • 7 Bilgi University, Department of Genetics and Bioengineering, Istanbul, Turkey.
  • 8 Baskent University School of Medicine, Dept. of Immunology, Adana Dr. Turgut Noyan Medical and Research Center, Adana, Turkey. ozgurkutuk@sabanciuniv.edu.
PMID: 34294688 DOI: 10.1038/s41420-021-00573-2
Abstract

Breast Cancer is the most common Cancer with a high rate of mortality and morbidity among women worldwide. Estrogen Receptor status is an important prognostic factor and endocrine therapy is the choice of first-line treatment in ER-positive breast Cancer. However, most tumors develop resistance to endocrine therapy. Here we demonstrate that BH3 profiling technology, in particular, dynamic BH3 profiling can predict the response to endocrine therapy agents as well as the development of acquired resistance in breast Cancer cells independent of Estrogen Receptor status. Immunofluorescence analysis and subcellular fractionation experiments revealed distinct ER-α and ER-β subcellular localization patterns in breast Cancer cells, including mitochondrial localization of both receptor subtypes. shRNA-mediated depletion of ER-β in breast Cancer cells led to resistance to endocrine therapy agents and selective reconstitution of ER-β in mitochondria restored sensitivity. Notably, mitochondria-targeted ER-α did not restore sensitivity, even conferred further resistance to endocrine therapy agents. In addition, expressing mitochondria-targeted ER-β in breast Cancer cells resulted in decreased mitochondrial respiration alongside increased total ROS and mitochondrial superoxide production. Furthermore, our data demonstrated that mitochondrial ER-β can be successfully targeted by the selective ER-β agonist Erteberel. Thus, our findings provide novel findings on mitochondrial estrogen signaling in breast Cancer cells and suggest the implementation of the dynamic BH3 technique as a tool to predict acquired endocrine therapy resistance.

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