Tumoral Docosahexaenoic Acid Content of 5% Improved Chemotherapy Efficacy in Mice Bearing Patient Derived Breast Cancer Xenografts Via the Necroptosis Pathway

Susan Goruk, Vera Mazurak, Lynne M Postovit, Catherine J. Field

University of Alberta; University of Alberta; University of Alberta; University of Alberta

Docosahexaenoic acid (DHA) enhances the action of relevant cytotoxic drugs and reduces the growth of immortalized breast cancer cell lines in vitro and in vivo. We sought to confirm this in a more clinically translatable heterogeneic model, using breast cancer patient derived xenografts (PDXs). Female NSG mice bearing triple negative breast cancer PDX tumors (100 mm3) were randomized to one of two nutritionally adequate high fat diets (20% w/w ± DHA). Treatment paradigms included a) control (0% dietary DHA); b) control+ docetaxel (TXT 5mg/kg; intraperitoneal) and c) 4% w/w of fat DHA+ TXT (n=7/group). After 6 weeks of chemotherapy, tumors were excised, weighed and the phospholipid fatty acid composition determined. Feeding 4% DHA decreased tumor growth by 43% and 34% compared to control or control+TXT, respectively (P<0.05) and increased tumor phospholipid DHA compared to control+TXT (5.7 ± 0.3% vs 3.8 ± 0.2%, P<0.05). We further sought to determine the mechanisms through which DHA elicits this anti-tumor effect. An increase in necrotic tissue was observed in immunohistochemical haematoxylin and eosin (H and E) staining of the DHA+TXT tumors compared to both control diet groups. Protein analysis confirmed a higher expression of proteins involved in necroptosis: Ripk1, Ripk3 and MLKL, coinciding with a lower NFκB protein expression in tumors from the DHA+TXT group (P<0.05). This study suggests, that feeding a diet supplemented with DHA facilitates the anti-cancer effect of TXT on breast cancer PDXs, at least in part, through increased necroptosis. (supported by CIHR)