Abstract 2572: γ-Tocotrienol inhibition of androgen receptor (AR) expression and activation in triple negative breast cancer (TNBC) MBA-MB-231 and MDA-MB-453 cells is associated with a reduction in proliferation, migration and epithelial-to-mesenchymal transition (EMT)

Abstract

Triple negative breast cancer (TNBC) is an aggressive invasive malignancy with the lowest 5-years survival rate. Gene expression profiling indicates that TNBC is a heterogeneous disease and at present, there is no targeted therapy available for treatment. Approximately one third of TNBC expressed androgen receptor (AR) and evaluation of AR positive TNBC primary tumors shows nuclear localization of AR, an indication of transcriptionally active receptors. AR levels are most abundant in the luminal AR (LAR) molecular subtype of TNBC, but other non-LAR molecular TNBC subtypes also display high levels of AR expression and activity. Previous studies have shown that AR inhibition or AR knockdown significantly reduces baseline proliferation, anchorage-independent growth, migration and invasion and increase apoptosis in different TNBC cell lines. γ-Tocotrienol is a natural isoform of vitamin E that displays potent anticancer activity. Studies were conducted to determine if γ-tocotrienol effects on AR levels and activity play a role in mediating γ-tocotrienol induced inhibition of TNBC cell proliferation, migration and epithelial-to-mesenchymal transition (EMT). In vitro studies showed that treatment with 0-12 μM γ-tocotrienol induced a dose-responsive significant decrease in TNBC MDA-MB-231 and MDA-MB-453 cell proliferation and viability. Treatment with 35 nM dihydrotestosterone (DHT) resulted in an increase of AR expression and corresponding increase in the growth of both TNBC cell lines. Treatment of MDA-MB-231 and MDA MB-453 cells with γ-tocotrienol (5 μM and 7 μM, respectively), significantly inhibited DHT-induced proliferation of both TNBC cell lines. Western blot analysis showed that γ-tocotrienol treatment significantly reduced DHT-induced cytoplasmic and nuclear AR expression in MDA-MB-453 cells, but induced only a slight and insignificant reduction in AR expression in MDA-MB-231 cells. Immunocytochemistry studies confirmed that γ-tocotrienol treatment induced a decrease in cytoplasmic and nuclear AR expression in both TNBC cell lines, but this decrease was only found to be significant in MDA-MB-453 cells. Other studies showed that γ-tocotrienol treatment significantly reduced cancer cell migration and this finding was associated with an increased expression in cytokeratin 8 (an epithelial cell biomarker) and decrease in vimentin (a mesenchymal cell biomarker) in both TNBC cell lines, and is an indication of a reversal in EMT. In summary, these results demonstrated that γ-tocotrienol treatment inhibits AR expression as well as DHT-dependent cell proliferation, migration and EMT in TNBC. These findings also suggest that AR may be a potential therapeutic target for the treatment of both LAR and non-LAR TNBC subtypes. Citation Format: Tasmin A. Sultana, Nayef Aldabaan, Paul W. Sylvester. γ-Tocotrienol inhibition of androgen receptor (AR) expression and activation in triple negative breast cancer (TNBC) MBA-MB-231 and MDA-MB-453 cells is associated with a reduction in proliferation, migration and epithelial-to-mesenchymal transition (EMT) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2572.