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Estrogen Enhances the Expression of the Polyunsaturated Fatty Acid Elongase Elovl2 via ERa in Breast Cancer Cells
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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Number of Authors: 52016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0164241Article in journal (Refereed) Published
Abstract [en]

Endocrine therapy is the first-line targeted adjuvant therapy for hormone-sensitive breast cancer. In view of the potential anticancer property of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) together with chemotherapy in estrogen receptor alpha (ER alpha) positive mammary tumors, we have explored the regulation by estradiol of the fatty acid desaturation and elongation enzymes involved in DHA synthesis in the human breast cancer cell line MCF7, which expresses ER alpha but not ER beta. We demonstrate a robust up-regulation in the expression of the fatty acid elongases Elovl2 and Elovl5 upon estradiol stimulation in MCF7 cells, which was sustained for more than 24 hours. Exposure with the ER inhibitor tamoxifen abolished specifically the Elovl2 but not the Elovl5 expression. Similarly, knockdown of ER alpha eliminated almost fully the Elovl2 but not the Elovl5 expression. Furthermore, ER alpha binds to one specific ERE within the Elovl2 enhancer in a ligand dependent manner. The involvement of ER alpha in the control of especially Elovl2, which plays a crucial role in DHA synthesis, may have potential implications in the treatment of breast cancer.

Place, publisher, year, edition, pages
2016. Vol. 11, no 10, article id e0164241
National Category
Biological Sciences
Research subject
Physiology
Identifiers
URN: urn:nbn:se:su:diva-137515DOI: 10.1371/journal.pone.0164241ISI: 000389604900014OAI: oai:DiVA.org:su-137515DiVA, id: diva2:1066425
Available from: 2017-01-18 Created: 2017-01-09 Last updated: 2017-11-29Bibliographically approved
In thesis
1. ELOVL2 and PUFA biosynthesis: Impact on sex-specific processes in mammals
Open this publication in new window or tab >>ELOVL2 and PUFA biosynthesis: Impact on sex-specific processes in mammals
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Endogenously synthesized PUFAs (Polyunsaturated Fatty Acids) vary in production depending on medical conditions, gender, developmental phase, age, fertility status, pregnancy and lactation. PUFA biosynthesis is further regulated via amount of dietary intake as well as genetically. A key player in the PUFA biosynthesis enzyme machinery is the fatty acid elongase Elongation of very long-chain fatty acids 2 (ELOVL2) that is essential for the production of the omega-3 PUFA docosahexaenoic acid (DHA, 22:6 n-3) that has many beneficial health effects. In the omega-6 PUFA series, ELOVL2 produces docosapentaenoic acid (DPA n-6, 22:5 n-6). Specifically, ELOVL2 enables the elongation of PUFA with 22 carbons to generate precursors of 24 carbons for the generation of the previously mentioned end products as well as very long-chain (VLC) PUFA up to C34.

This thesis elucidates that estrogen has the power to modulate ELOVL2 expression in breast cancer cells and that this probably is due to ligand dependent binding of the estrogen receptor alpha (ERα) to the Elovl2 enhancer. In addition, estrogen via ERα modulates hepatic levels of Elovl2 in mice in a gender specific manner. Ablation of Elovl2 leads to whole body deficiency of DHA. The thesis unravels that systemic DHA levels in neonatal mice is determined both by the ELOVL2 status of the mother and the offspring. Ablation of Elovl2 also leads to impaired spermatogenesis and infertility in male mice. However, heterozygous Elovl2-ablated mice, differ in fertility potency depending on strain. Here we show that this discrepancy is linked to an altered ratio between saturated and mono-unsaturated fatty acids and VLC-PUFA moieties of glucosylceramides in testis.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2016. p. 64
National Category
Biophysics
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-134356 (URN)978-91-7649-549-0 (ISBN)978-91-7649-550-6 (ISBN)
Public defence
2016-11-15, Vivi Täckholmsalen (Q-salen), NPQ-huset, Svante Arrhenius väg 20, Stockholm, 10:00 (English)
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Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Accepted. Paper 2: Manuscript. Paper 3: Manuscript. Paper 4: Manuscript.

Available from: 2016-10-21 Created: 2016-10-05 Last updated: 2017-08-14Bibliographically approved

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