Abstract
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 (ERα) 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 ERα but not ERβ. 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, knock-down of ERα eliminated almost fully the Elovl2 but not the Elovl5 expression. Furthermore, ERα binds to one specific ERE within the Elovl2 enhancer in a ligand dependent manner. The involvement of ERα in the control of especially Elovl2, which plays a crucial role in DHA synthesis, may have potential implications in the treatment of breast cancer.
Highlights
Docosahexaenoic acid (DHA, 22:6) is an omega-3 polyunsaturated fatty acid (PUFA), which is abundant in fatty fish and other marine sources and has been shown to have a variety of health benefits on breast cancer both in rodents and humans [1] as well as in cell lines [2]
To assess if estrogen has the potential to regulate PUFA and especially docosahexaenoic acid (DHA) synthesis via regulating the expression of Elovl2, Elovl5, Fads1 and Fads2, MCF7 cells were treated for six hours with the estrogen receptors (ERs) ligand E2
While the effects of dietary DHA have been extensively studied, research in the past shows that there is a significant genetic component linked to endogenous PUFA concentrations in humans indicating that understanding the regulation of enzymes involved in PUFA synthesis is of great physiological importance
Summary
Docosahexaenoic acid (DHA, 22:6) is an omega-3 polyunsaturated fatty acid (PUFA), which is abundant in fatty fish and other marine sources and has been shown to have a variety of health benefits on breast cancer both in rodents and humans [1] as well as in cell lines [2]. The involved enzymes are located in the endoplasmatic reticulum and include the fatty acid desaturases 1 (FADS1) and 2 (FADS2) and the fatty acid elongases elongation of very long-chain fatty acids 2 (ELOVL2) and 5 (ELOVL5) where ELOVL2 is considered to be essential for the formation of C24 PUFAs in a tissue specific manner prior to further desaturation and β-oxidation of 24:6n-3 into DHA [4,5,6]. The connection between steroidal hormones such as estrogen and PUFA synthesis has previously been studied showing that hepatic Fads expression was up regulated in response to increased progesterone and 17-β-estradiol (E2) concentrations in female rats, followed by increased levels of long chain PUFAs [7]. ERs are part of the nuclear receptor superfamily of transcription factors and have important implications in hormone-related disorders, development and physiology [10]
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