Triple negative breast cancer (TNBC) is a heterogeneous disease entity with inferior outcomes to those of other subtypes. The androgen receptor (AR) is present in up to 30% of patients with TNBC.
In this study, we investigated the effect of bromodomain inhibitor (BETi), JQ1 combined with AR targeted therapy in AR positive TNBC. The activity of enzalutamide, anti-androgen drug was moderate with IC50 >10μM even in AR strong positive MDA-MB-453 TNBC cell line. JQ1 demonstrated significant anti-tumor activity in TNBC cell lines (MDA-MB-231, MDA-MB-453, MDA-MB-468, BT-20) and IC50 values were in 0.2-0.3μM range.
JQ1 induced apoptosis in a dose-dependent manner, evidenced by increased levels of cleaved caspase 3, caspase 9, and PARP. Further, JQ1 treatment induced G0-G1 arrest and downregulation of cyclin E1 and cyclin A2. The treatment of JQ1 reduced cell viability synergistically when combined with enzalutamide in AR expressing TNBC cell lines. After JQ1 treatment, MYC expression had significantly reduced over 72 hrs. In addition, ATAD2, a conserved factor harboring both ATPase domain and a bromodomain, expression levels were significantly repressed with JQ1 treatment in both cell lines. Suppression of ATAD2 was more significant when JQ1 was treated in siRNA of AR treated TNBC cells.
Taken together, our study showed that BET inhibitor with AR targeting strategy is a promising new therapeutic option for AR positive TNBC. Further studies including in vivo analysis is planned.
Clinical trial identification
Legal entity responsible for the study
In Hae Park
All authors have declared no conflicts of interest.