ANDROGEN RECEPTOR NEGATIVELY REGULATES ACSL4 TRANSCRIPTION IN BREAST CANCER CELLS

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

Mendoza

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

SAIB

Acyl-CoA synthetase 4 (ACSL4) is an enzyme involved in arachidonic acid metabolism. ACSL4 overexpression is known to play a key role in the development of aggressive prostate and breast cancer. In prostate cancer, it has been shown that inhibition of the androgen receptor (AR) leads to overexpression of ACSL4, suggesting that this enzyme may have an important role in these hormone-resistant tumors. Actually, AR signaling is emerging as an important factor in the pathogenesis of breast cancer. Several studies imply that AR may be a new marker and a potential therapeutic target among AR-positive breast cancer patients. The objective 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 ACSL4 whereas the quadruple negative MDA-MB-231 cell line contains high expression of this enzyme. In this context, we verified that high levels of AR mRNA are present in MCF-7 cells and absent in the highly aggressive cell line MDA-MB-231. In a bioinformatic analysis performed with Genomatix software on a 1.8 kb fragment of the human ACSL4 promoter, we identified a consensus site for 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 with 10 nM dihydrotestosterone (DHT) in steroid-free medium showed a reduction of promoter transcriptional activity and of ACSL4 mRNA levels, both in MCF-7 and in MDA-MB-231 cells transiently transfected with human AR. No effect of DHT was observed in control MDA-MB-231. Furthermore, as previously described in a prostate cancer model, in MCF-7 and MDA-MB-231 cells with 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 AR together with ACSL4 inhibitors in breast cancer.