Obesity induces chronic inflammation and is an established risk and progression factor for triple-negative breast cancers, including basal-like (BL) and claudin-low (CL) subtypes. We tested the effects of dietary supplementation with ethyl esters of the marine-derived anti-inflammatory omega-3 fatty acids eicosapentaenoic and docosahexaenoic acid (EPA+DHA; Lovaza®) on growth of murine BL and CL mammary tumors. Female ovariectomized C57BL/6 mice were fed a control diet or a diet-induced obesity (DIO) diet with or without EPA+DHA (0.025%, resulting in blood levels of EPA and DHA comparable to women taking Lovaza 4 g/day) for 6 weeks. All mice were then orthotopically injected with Wnt-1 cells (a BL tumor cell suspension derived from MMTV-Wnt-1 transgenic mouse mammary tumors) or M-Wnt cells (a CL tumor cell line cloned from the Wnt-1 tumor cell suspension). Mice were killed when tumors were 1 cm in diameter. EPA+DHA supplementation did not significantly impact Wnt-1 or M-Wnt mammary tumor growth in normoweight control mice. However, EPA+DHA supplementation in DIO mice reduced growth of Wnt-1 and M-Wnt tumors; reduced leptin:adiponectin ratio and pro-inflammatory eicosanoids in the serum; improved insulin sensitivity; and decreased tumoral expression of cyclooxygenase-2 and phospho-p65. Thus, EPA+DHA supplementation in mouse models of postmenopausal BL and CL breast cancer offsets many of the pro-tumorigenic effects of obesity. These preclinical findings, in combination with results from parallel biomarker studies in women, suggest EPA+DHA supplementation may reduce the burden of BL and CL breast cancer in obese women.

The prescription drug Lovaza® contains ethyl esters of the marine based omega 3 fatty acids docosahexaenoic acid (DHA; 38% w/w) and eicosapentanoic acid (EPA; 47%) which play major roles in inflammation, cell membrane fluidity and cell signaling. The effects of omega‐3 fatty acid supplementation on ER‐negative basal‐like and claudin‐low breast tumors, which are aggressive subtypes with poor prognoses, are not well characterized. Furthermore, the ability of EPA and DHA to offset the enhancing effects of obesity on these cancers is unknown. Female C57BL/6 mice were fed either a control (AIN‐76A) diet, diet‐induced obesity regimen (DIO; 60 kcal % fat diet), or DIO diet + Lovaza (2.5g / kg) for 6 weeks. All mice were then orthotopically injected with a tumor cell suspension derived from MMTV‐Wnt‐1 mammary tumors (Wnt‐1 basal‐like) or a clonal isolate from the same tumors shown to have a molecular profile similar to human claudin‐low breat tumors (M‐Wnt claudin low). Tumors were allowed to grow until one or more tumors reached 1 cm in diameter in any direction and then mice were killed and tumors were paraffin embedded or snap frozen for further analysis. Wnt‐1 and M‐Wnt mammary tumor weight was significantly reduced by Lovaza supplementation in obese mice in parallel with enhanced cellular apoptosis. This work was supported by a Breast Cancer Research Foundation Grant and Glaxo‐Smith Kline donated the Lovaza® capsules.Grant Funding Source: Breast Cancer Research Fund