Abstract
Triple-negative breast cancer (TNBC) is a heterogeneous disease comprising several subtypes. Androgen-receptor (AR) signaling has been targeted by several investigational agents in luminal AR subtype TNBCs. Bromodomain (BRD) and extra-terminal motif (BET) protein inhibitors have been shown to attenuate AR signaling in metastatic castration-resistant prostate cancer and to overcome enzalutamide resistance. We demonstrated potent anti-tumor effects of the BET inhibitor JQ1 against AR-positive TNBC cell lines using cell viability and cell cycle analysis. To reveal the mechanisms of JQ1 effects, multiplex gene expression analysis and immunoblotting assays were used. We examined in vivo effects of JQ1 in a xenograft model of AR expressing TNBC. JQ1 exhibited its anti-proliferative activity by inducing apoptosis and cell cycle arrest. JQ1 activity was not mediated by MYC downregulation. Instead, JQ1 blocked the interactions among the ATPase-family AAA-domain-containing 2 protein (ATAD2), BRD2, BRD4, and AR; effectively suppressing the expression of AR associated targets. In addition, JQ1 showed significant anti-tumor activity in vivo in TNBC xenograft mouse models as a monotherapy and in combination with anti-AR therapy. Taken together, our results showed that the BET inhibitor JQ1 is a promising therapeutic agent for the treatment of AR-positive TNBC.
Highlights
Triple-negative breast cancer (TNBC) accounts for ~20% of metastatic breast cancer[1]
To explore the correlation between enzalutamide sensitivity and AR expression, we evaluated AR transcript and protein abundance in selected TNBC cell lines (Supplemental Fig. 1a–c)
Cell lines not expressing AR did not respond to enzalutamide treatment (Supplemental Fig. 2)
Summary
Triple-negative breast cancer (TNBC) accounts for ~20% of metastatic breast cancer[1]. The luminal androgen-receptor (LAR) subtype, accounting for ~20% of TNBCs, demonstrates increased expression of mRNA encoding the androgen receptor (AR), enhancing AR-signaling sensitive to AR antagonists[3]. Considering the complexity of AR signaling and crosstalk in AR + breast cancer, AR antagonists have been investigated in combination with other targeted therapies. Such studies have focused on elucidating the mechanisms of primary and secondary resistance to AR inhibitors and on improving the efficacy of AR inhibitors in AR + breast cancers[13]. BRD4 interacts with the N-terminal domain of AR and induces AR-mediated gene transcription and BET inhibitor, JQ1 effectively disrupts the interaction between BRD4 and AR leading to cytotoxic efficacies in advanced prostate cancer model[17]. We assessed the ability of the BET inhibitor JQ1 to enhance the efficacy of AR blockade in AR-expressing TNBCs
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