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Estrogen Enhances the Expression of the Polyunsaturated Fatty Acid Elongase Elovl2 via ER? in Breast Cancer Cells.

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 (ER?) 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? but not ER?. 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 ER? eliminated almost fully the Elovl2 but not the Elovl5 expression. Furthermore, ER? binds to one specific ERE within the Elovl2 enhancer in a ligand dependent manner. The involvement of ER? in the control of especially Elovl2, which plays a crucial role in DHA synthesis, may have potential implications in the treatment of breast cancer.

SUBMITTER: Gonzalez-Bengtsson A

PROVIDER: S-EPMC5082882 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Estrogen Enhances the Expression of the Polyunsaturated Fatty Acid Elongase Elovl2 via ERα in Breast Cancer Cells.

González-Bengtsson Amanda A Asadi Abolfazl A Gao Hui H Dahlman-Wright Karin K Jacobsson Anders A

PloS one 20161027 10

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. W ...[more]

PMID: 27788154

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Project description:BackgroundΔ6-Desaturase (Fads2) is widely regarded as rate-limiting in the conversion of dietary α-linolenic acid (18:3n-3; ALA) to the long-chain omega-3 polyunsaturated fatty acid docosahexaenoic acid (22:6n-3; DHA). However, increasing dietary ALA or the direct Fads2 product, stearidonic acid (18:4n-3; SDA), increases tissue levels of eicosapentaenoic acid (20:5n-3; EPA) and docosapentaenoic acid (22:5n-3; DPA), but not DHA. These observations suggest that one or more control points must exist beyond ALA metabolism by Fads2. One possible control point is a second reaction involving Fads2 itself, since this enzyme catalyses desaturation of 24:5n-3 to 24:6n-3, as well as ALA to SDA. However, metabolism of EPA and DPA both require elongation reactions. This study examined the activities of two elongase enzymes as well as the second reaction of Fads2 in order to concentrate on the metabolism of EPA to DHA.Methodology/principal findingsThe substrate selectivities, competitive substrate interactions and dose response curves of the rat elongases, Elovl2 and Elovl5 were determined after expression of the enzymes in yeast. The competitive substrate interactions for rat Fads2 were also examined. Rat Elovl2 was active with C(20) and C(22) polyunsaturated fatty acids and this single enzyme catalysed the sequential elongation reactions of EPA→DPA→24:5n-3. The second reaction DPA→24:5n-3 appeared to be saturated at substrate concentrations not saturating for the first reaction EPA→DPA. ALA dose-dependently inhibited Fads2 conversion of 24:5n-3 to 24:6n-3.ConclusionsThe competition between ALA and 24:5n-3 for Fads2 may explain the decrease in DHA levels observed after certain intakes of dietary ALA have been exceeded. In addition, the apparent saturation of the second Elovl2 reaction, DPA→24:5n-3, provides further explanations for the accumulation of DPA when ALA, SDA or EPA is provided in the diet. This study suggests that Elovl2 will be critical in understanding if DHA synthesis can be increased by dietary means.

Dataset Information

Estrogen Enhances the Expression of the Polyunsaturated Fatty Acid Elongase Elovl2 via ER? in Breast Cancer Cells.

Publications

Estrogen Enhances the Expression of the Polyunsaturated Fatty Acid Elongase Elovl2 via ERα in Breast Cancer Cells.

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