12P - BET inhibitors induce apoptosis through ATAD2 suppression in AR positive triple negative breast cancer cells (12P)

Date 18 November 2017
Event ESMO Asia 2017 Congress
Session Poster lunch
Topics Basic Science
Presenter HANNA YANG
Citation Annals of Oncology (2017) 28 (suppl_10): x1-x6. 10.1093/annonc/mdx652
Authors H. YANG1, S.H. Shim2, K.S. Lee2, I.H. Park1
  • 1Translational Cancer Research Branch, Division Of Cancer Biology, Research Institute, National Cancer Center, 10408 - Gyeonggi-do/KR
  • 2Center For Breast Cancer, National Cancer Center Hospital,, National Cancer Center, 10408 - Gyeonggi-do/KR

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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

not applicable

Legal entity responsible for the study

In Hae Park

Funding

None

Disclosure

All authors have declared no conflicts of interest.