Chemoprevention of Breast Cancer by Fish Oil in Preclinical Models: Trials and Tribulations

Signori, Carina; El‐Bayoumy, Karam; Russo, José; Thompson, Henry J.; Richie, John P.; Hartman, Terryl J.; Manni, Andrea

doi:10.1158/0008-5472.can-11-0977

Cited by 51 publications

(50 citation statements)

References 25 publications

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“…Since breast cancer requires the coordinated activation of multiple cellular mechanisms, a multi-targeted approach is needed to prevent the development of mammary carcinogenesis. We have been interested in testing the combination of antiestrogens with n-3FA, an attractive class of compounds that could potentiate the beneficial effects of antiestrogens by inhibiting multiple cellular pathways potentially involved in mammary carcinogenesis (for review, see Signori et al 1 ). We believe that a major attractive feature of this approach is its safety since it allows us to combine a lower and hence less toxic dose of antiestrogens with n-3FA, compounds that are known to have inherent health benefits (that is, reduction in cardiovascular risk) beyond their potential chemopreventive benefit in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…1 While basic mechanisms are under investigation using preclinical models of mammary carcinogenesis, [2][3][4] we are testing concomitantly the clinical relevance of this approach in postmenopausal women using surrogate markers of breast cancer development (NCT00723398). While the primary end point of our clinical trial is a reduction in breast density, a wellestablished risk factor for breast cancer, 5 we are also examining the effects of the individual and combined administration of Ral and n-3FA on several biomarkers thought to be potentially involved in mammary carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Administration of omega-3 fatty acids and Raloxifene to women at high risk of breast cancer: interim feasibility and biomarkers analysis from a clinical trial

et al. 2012

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BACKGROUND/OBJECTIVES:The antiestrogen, Raloxifene (Ral) is an effective breast cancer chemopreventive agent. Omega-3 fatty acids (n-3FA) may inhibit mammary carcinogenesis. On the basis of their mechanisms of action, we test the hypothesis that a combination of n-3FA and Ral may be superior in reducing select biomarkers of breast cancer risk in women. SUBJECTS/METHODS: Postmenopausal women at increased risk for breast cancer (breast density X25%) were randomized to: (1) no intervention; (2) Ral 60 mg; (3) Ral 30 mg; (4) n-3FA (Lovaza) 4 g and (5) Lovaza 4 g þ Ral 30 mg for 2 years. Reduction in breast density is the primary end point of the study. We report preliminary data on feasibility, compliance and changes in secondary end points related to IGF-I signaling, estrogen metabolism, oxidative stress and inflammation in the first group of 46 women who completed 1 year of the study. RESULTS: All interventions were well tolerated with excellent compliance (96 ± 1% overall) by pill count and also supported by the expected rise in both serum n-3FA and n-3FA/Omega-6 fatty acids (n-6FA) ratio in women randomized to groups 4 and 5 (Po0.05). Lovaza decreased serum triglycerides and increased high-density lipoprotein (HDL) cholesterol compared with control (Po0.05 for both). Ral reduced serum IGF-1 in a dose-dependent manner (Po0.05) while Lovaza did not. Lovaza had no effect on IGF-1 or IGFBP-3. None of the other biomarkers were affected by our treatment. CONCLUSION: The combination of Lovaza and Ral is a feasible strategy that may be recommended in future breast cancer chemoprevention trials.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Administration of omega-3 fatty acids and Raloxifene to women at high risk of breast cancer: interim feasibility and biomarkers analysis from a clinical trial

et al. 2012

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“…A review of 81 rodent studies concluded that dietary omega-6 fatty acids dose-dependently accelerate mammary tumorigenesis (11). Conversely, dietary EPA and DHA prevent mammary tumor development in animals (12)(13)(14)(15). The effect of omega-3 and omega-6 intake on breast cancer risk in humans has not been determined.…”

Section: Introductionmentioning

confidence: 99%

Omega-3 and Omega-6 Fatty Acids in Blood and Breast Tissue of High-Risk Women and Association with Atypical Cytomorphology

Hidaka

Harvey

et al. 2015

Cancer Prevention Research

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The ratio of omega-3 to omega-6 fatty acids, especially the longchain eicosapentaenoic acid (EPA) þ docosahexaenoic acid (DHA) to arachidonic acid (AA) ratio, is inversely associated with breast cancer risk. We measured the association between cytologic atypia, a biomarker for short-term risk of breast cancer development, and omega-3 and omega-6 fatty acid intake and levels in blood and breast tissue. Blood and benign breast tissue, sampled by random periareolar fine-needle aspiration (RPFNA), was obtained from 70 women at elevated risk for breast cancer. Self-reported dietary intake was assessed by the NCI's Food Frequency Questionnaire. The fatty acid composition of five lipid compartments, red blood cell, plasma and breast phospholipids, and plasma and breast triaclyglycerides (TAG), was analyzed by gas chromatography as weight percent. Median daily intakes of EPAþDHA and total omega-3 fatty acids were 80 mg and 1.1 g, respectively. The median total omega-3:6 intake ratio was 1:10. Compared with women without atypia, those with cytologic atypia had lower total omega-3 fatty acids in red blood cell and plasma phospholipids and lower omega-3:6 ratios in plasma TAGs and breast TAGs (P < 0.05). The EPAþDHA:AA ratio in plasma TAGs was also lower among women with atypia. This is the first report of associations between tissue levels of omega-3 and omega-6 fatty acids and a reversible tissue biomarker of breast cancer risk. RPFNA cytomorphology could serve as a surrogate endpoint for breast cancer prevention trials of omega-3 fatty acid supplementation. Cancer Prev Res; 8(5); 359-64. Ó2015 AACR.

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“…It has been postulated that the risk of breast cancer can be influenced by certain dietary components such as the amount and type of dietary fats ingested (3)(4)(5)(6)(7). Among the fatty acids, omega-3 (n-3) and omega-6 (n-6) fatty acids have been suggested to decrease and increase breast cancer risk, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…Among the fatty acids, omega-3 (n-3) and omega-6 (n-6) fatty acids have been suggested to decrease and increase breast cancer risk, respectively. Despite the prevailing hypothesis that the ratio of n-3:n-6 may be important for chemoprevention, the optimum ratio has not been rigorously tested in many previously published reports (7). Furthermore, several chemoprevention studies in animal models used diets that were high in the percent of dietary calories provided from fat which are not consistent with the U.S. Dietary Guidelines (8).…”

Section: Introductionmentioning

confidence: 99%

Proteomic Changes Induced by Effective Chemopreventive Ratios of n-3:n-6 Fatty Acids and Tamoxifen against MNU-Induced Mammary Cancer in the Rat

Skibinski

Thompson

Das

et al. 2013

Cancer Prevention Research

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We used a proteomic approach to gain insights into the mechanisms of protection at the protein level by a high n-3:n-6 ratio in the absence and presence of Tamoxifen. Four groups were treated with 1-methyl-1-nitrosourea (MNU) and fed the following diets with varied n-3:n-6 ratios; group 1 ¼ 1:1; groups 2 and 3 ¼ 10:1 and 25:1, respectively; group 4: (25:1) plus Tamoxifen (1 mg/kg diet). The plasma from six rats/group was pooled and analyzed with the isobaric tags for relative and absolute quantitation method; 148 proteins were identified with 95% confidence by ProteinPilot 4.0. In plasma of rats fed 10:1, 25:1 n-3:n-6, and 25:1 plus Tamoxifen, the number of proteins that met our criteria (P 0.05, error factor 2) were 10, 14, and 19 proteins, respectively. Selected proteins were further validated by Western blotting. Compared to 1:1, both 10:1 and 25:1 diets upregulated vitamin D binding protein, gelsolin, and 14-3-3 sigma, reported to have tumor suppressive effects, whereas alpha-1B-glycoprotein, which has been reported to be elevated in the serum of breast cancer patients was decreased. Compared to 25:1, the 25:1 plus Tamoxifen diet downregulated apolipoprotein E, haptoglobin, and inter-a-inhibitor H4 heavy chain. Ingenuity pathway analysis determined that the trends of specific proteins were related to lipid metabolism in the 25:1 n-3:n-6 group, whereas the 25:1 n-3:n-6 plus Tamoxifen group included proteins involved in cancer and inflammation. Our results show that several proteins were altered in a manner consistent with chemoprevention. Such proteins may serve as biomarkers to monitor efficacy of n-3 and Tamoxifen in future clinical chemoprevention trials. Cancer Prev Res; 6(9); 979-88. Ó2013 AACR.

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Chemoprevention of Breast Cancer by Fish Oil in Preclinical Models: Trials and Tribulations

Cited by 51 publications

References 25 publications

Administration of omega-3 fatty acids and Raloxifene to women at high risk of breast cancer: interim feasibility and biomarkers analysis from a clinical trial

Administration of omega-3 fatty acids and Raloxifene to women at high risk of breast cancer: interim feasibility and biomarkers analysis from a clinical trial

Omega-3 and Omega-6 Fatty Acids in Blood and Breast Tissue of High-Risk Women and Association with Atypical Cytomorphology

Proteomic Changes Induced by Effective Chemopreventive Ratios of n-3:n-6 Fatty Acids and Tamoxifen against MNU-Induced Mammary Cancer in the Rat

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