ANDROGEN RECEPTOR NEGATIVELY REGULATES ACSL4 TRANSCRIPTION IN BREAST CANCER CELLS

DATTILO, MELINA A.; LOPEZ PAULA; ADLER, EVELYN; BENZO YANINA; BIGI, MARÍA M.; CORNEJO MACIEL FABIANA; CRISTINA PAZ; ERNESTO J. PODESTÁ; PAULA MARIANA MALOBERTI

Congreso; LVIII Annual Meeting of the Argentine Society for Biochemistry and Molecular Biology Research; 2022

Acyl-CoA synthetase 4 (ACSL4) is an enzyme involved in arachidonic acid metabolism. ACSL4 overexpression is known to playa key role in the development of aggressive prostate and breast cancer. In prostate cancer, it has been shown that inhibition of theandrogen receptor (AR) leads to overexpression of ACSL4, suggesting that this enzyme may have an important role in thesehormone-resistant tumors. Actually, AR signaling is emerging as an important factor in the pathogenesis of breast cancer. Severalstudies imply that AR may be a new marker and a potential therapeutic target among AR-positive breast cancer patients. Theobjective of this work is to study whether androgenic regulation is involved in ACSL4 transcription in breast cancer cells.We previously demonstrated that the hormone receptor-positive MCF-7 breast cancer cell line expresses low levels of ACSL4whereas the quadruple negative MDA-MB-231 cell line contains high expression of this enzyme. In this context, we verified thathigh levels of AR mRNA are present in MCF-7 cells and absent in the highly aggressive cell line MDA-MB-231. In a bioinformaticanalysis performed with Genomatix software on a 1.8 kb fragment of the human ACSL4 promoter, we identified a consensus sitefor the AR with a score close to 1. This finding was also confirmed with the Alggen Promo tool. AR overexpression in MDA-MB231 cell line results in a reduction of ACSL4 promoter activity measured by NanoGlo luciferase reporter gene assay. Moreover,we also observed a decrease in mRNA expression of ACSL4 in MDA-MB-231 overexpressing AR. Breast cancer cells treated with10 nM dihydrotestosterone (DHT) in steroid-free medium showed a reduction of promoter transcriptional activity and of ACSL4mRNA levels, both in MCF-7 and in MDA-MB-231 cells transiently transfected with human AR. No effect of DHT was observedin control MDA-MB-231. Furthermore, as previously described in a prostate cancer model, in MCF-7 and MDA-MB-231 cellswith ectopic AR expression, transcriptional activity of ACSL4 promoter was induced by 10 µM of the AR antagonist bicalutamide(Casodex). In summary, these results demonstrate that androgens could regulate ACSL4 expression in breast cancer cells.Therefore, in the future it would be important to evaluate the effectiveness of the combined use of therapies that target the ARtogether with ACSL4 inhibitors in breast cancer.