Abstract Background Ever since the discovery of the PI3K/Akt/mTOR pathway key role in breast cancer resistance, several molecules have been developed to target this pathway. However, mechanisms of resistance restrain their efficacy. An in-depth understanding of the interactions of PI3K pathway is essential to improve its blockade and avoid resistance. Preclinical studies reported that lipid composition of cancer cells altered the activation of PI3K pathway, thus suggesting another possible molecular interaction with lipid metabolism. The aim of this study was to analyze the relationship between the activation of PI3K pathway and tumor lipid composition in breast cancer patients. Methods Frozen and formalin-fixed paraffin-embedded tumor specimens were retrieved for 50 French patients with stage I to III primary breast cancer treated uniformly with surgery, adjuvant chemotherapy, radiation therapy and endocrine therapy. The tumor specimens were analyzed for PIK3CA gene mutation, PTEN protein expression by immunohistochemistry, and pAktS473, pAktT308, mTOR, pS6K, and S6RP by protein array. Tumor total fatty acid (FA) and phospholipid FA compositions were analysed using mass spectroscopy. Pearson test was used for correlation analyses. Results Mean age was 53 years. All tumors were ER or PR positive and HER-2 negative, and 76% were node positive. PI3K mutation was observed in 14% of cases, and 34% were PTEN negative or had low PTEN expression. Mean tumor satured fatty acid (SFA) level was 33.78 mol%, monounsaturated FA (MUFA) level was 46.46 mol%, n-6 polyunsaturated FA (PUFA) level was 18.08 mol%, and n-3 PUFA level was 1.68 mol%. Large and high grade tumors had a higher SFA content. MUFA rich tumors were frequently low grade. There was a positive correlation between d18:1/C20:0 ceramide level and Akt, mTOR and p70S6K expression. mTOR expression also correlated with 18:0 lysophosphatidylserine (lysoPS), 36:1 PS, 38:3 PS, 38:5 PS, 40:5 PS, 40:6 PS, 34:0 phosphatidylcholine (PC), 34:1 PC, and 38:3 PC. Conclusions Our results show that SFA associated with a more aggressive tumor phenotype and that PI3K pathway activation significantly correlated with fatty acid composition of specific tumor phospholipids. These results suggest a potential role of tumor lipid metabolism in PI3K pathway activation. Citation Format: Nawale Hajjaji, Flavie Arbion, Alain Fautrel, Claire Villalva, Lucie Karayan-Tapon, Marie-Lise Jourdan. Activation of PI3K pathway in breast cancer associates with tumor phospholipid fatty acid composition. [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 1051.
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