Abstract 4323: Dietary omega-3 suppress mammary tumor growth, metastasis and enhances survival in an iso-caloric pair-fed mice model
Authors: Khadge Saraswoti , Thiele Geoffrey M. , Klassen Lynell W. , Sharp Graham J. , McGuire Timothy R. , Duryee Michael J. , Britton Holly C. , Dafferner Alicia J. , Beck Jordan , Black Paul , DiRusso Concetta , Talmadge James E. 
Published: July 2016

Abstract
Omega-6 (ω6) and omega-3 (ω3) poly unsaturated fatty acids (PUFA) are pro- and anti-inflammatory respectively. Regulating their dietary ratio provides an approach for cancer prevention and potentially therapy; however, most studies have not separated the inflammatory effects of dietary fatty acids (FA) from that of obesity. Herein we studied the effects of the ω6:ω3 ratio in iso-caloric diets containing 35.5% of calories from fat on mammary tumor growth and metastasis. The ω6:ω3 ratio in ω6 and ω3 based diets were 42:1 and 1:1 respectively (confirmed by gas chromatography-mass spectrometry) using the liquid, Lieber DeCarli diet with fish oil substituting for 70% of olive oil. The ω3 diet contained 3:1 ratio of eicosapentaenoic acid (EPA) and docosahexaenoic (DHA) as major ω3 FA with small amount of linolenic acids. The ω6 diet contained linoleic acid as predominant ω6 FA and small level of linolenic acid as ω3 FA. The diets were pair-fed to avoid the tumor promoting effects of obesity. Two weeks after establishing female BALB/c mice on the diets, they were orthotopically injected with 4T1 mammary tumors. Outcomes included body weight, diet consumption, tumor growth, metastasis and survival. In association with pair feeding there were no significant differences in the diet consumed (ω3 diet used as baseline) and weight gain between animals; however, the time to tumor growth was significantly more rapid in mice fed the ω6 diet versus the ω3 diet cohorts. The ω6 diet fed cohort had significantly higher numbers of pulmonary and hepatic metastases and significantly shortened survival. Further, ω6 diet fed mice had an unusual metastasis profile including an increase in ovarian and renal metastases and an increase in posterior paralysis that in prior studies was associated with demineralization, osteolysis, marrow metastases and spontaneous long bone fractures in mice fed ω6-enriched diet. Histological analysis of tissues supported the observation of more frequent unusual metastasis sites (ovaries, kidneys, heart) along with systemic changes to myeloid cells infiltration in the tissues of mice fed ω6 diet. Further, ω6 and ω3 diets had identical total and fat calories and were pair fed; however, the tumors and livers of ω6 diet fed cohorts had more lipid content in adipocytes. Our results were replicative and also found to be consistent when the tumor growth and survival experiments were compared between young (22 weeks) versus old (58 weeks) mice in independent studies. In summary, our studies demonstrate that the dietary ratio of ω6:ω3 regulates tumor growth and metastasis.
Citation Format: Saraswoti Khadge, Geoffrey M. Thiele, Lynell W. Klassen, Graham J. Sharp, Timothy R. McGuire, Michael J. Duryee, Holly C. Britton, Alicia J. Dafferner, Jordan Beck, Paul Black, Concetta DiRusso, James E. Talmadge. Dietary omega-3 suppress mammary tumor growth, metastasis and enhances survival in an iso-caloric pair-fed mice model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4323.