Abstract 4419: HER2 expression and 17β-estradiol induce ACSL4 expression in estrogen receptor positive mammary carcinoma cells

Abstract

Abstract Breast cancer is a multifactorial disease involving several molecular changes and a high proliferation rate often under the activation of hormonal receptors. Therefore, cancer cells require the metabolic machinery for membrane synthesis and to promote signaling pathways. Amongst biomolecules required for efficient cell growth are polyunsaturated fatty acids, like arachidonic acid, that are essential nutrients whose cellular uptake is partly governed by long chain acyl-CoA synthetases (ACSL). In this study, we investigated the impact of 17β-estradiol and Human Epidermal growth factor Receptor 2 (HER2) on cellular uptake of polyunsaturated fatty acids and on the expression of ACSLs. The administration of 17β-estradiol in steroid-starved MCF-7 and T47D mammary carcinoma cells induced a significant increase in cellular uptake of arachidonic acid (AA) and eicosapentaenoic acid (EPA), and in ACSL4 protein content (p<0.05). There was no change in the expression of the ACSL1, ACSL3 and ACSL6 isoforms. Increased ACSL4 protein expression was not accompanied by changes in ACSL4 mRNA expression, but was associated with a significant increase in the protein half-life (T1/2=26±2h) compared to untreated cells (T1/2=8±0.5h). Silencing of ERα reversed the impact of 17β-estradiol on ACSL4 protein expression and half-life. Silencing of ACSL4 eliminated the 17β-estradiol-induced increase in cellular polyunsaturated fatty acid uptake, cell migration and invasion capacities. ACSL4 silencing also prevented the 17β-estradiol-induced increases in p-Akt and p-GSK3β, as well as the 17β-estradiol-induced decrease in E-cadherin expression, important events in epithelial to mesenchymal transition. In addition, the forced expression of HER2 in MCF7 cells induced an increase in cellular uptake of AA and in the expression of ACSL4 measured by both qPCR and western blots. This suggests that HER2-induces ACSL4 expression by a mechanism that differs from that of 17β-estradiol. Further investigations are planned to study the implication of ACSL4 on cellular functions induced by HER2. Overall, these results demonstrate that an induction of ACSL4 protein expression in ERα positive MCF-7 and T47D cells is implicated in 17β-estradiol-induced cellular migration and invasion capacities. Citation Format: Maroua Mbarik, Anissa Belkaid, Marc E. Surette. HER2 expression and 17β-estradiol induce ACSL4 expression in estrogen receptor positive mammary carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4419. doi:10.1158/1538-7445.AM2017-4419