Targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer

Xiaohong Xia,Zhiqiang Guo,Yanling Li,Chuyi Huang,Jinbao Liu,Xuejun Wang,Lili Jiang,Hongbiao Huang,Fangcheng Zhang,Yuan Liu,Ningning Liu,Yuning Liao

doi:10.1038/s41389-018-0086-y

Abstract

Estrogen receptor α (ERα) is expressed in ~67% of breast cancers and is critical to their proliferation and progression. The expression of ERα is regarded as a major prognostic marker, making it a meaningful target to treat breast cancer (BCa). However, hormone receptor-positive BCa was sometimes irresponsive or even resistant to classic anti-hormonal therapies (e.g., fulvestrant and tamoxifen). Hence, novel anti-endocrine therapies are urgent for ERα+ BCa. A phase II study suggested that bortezomib, an inhibitor blocking the activity of 20 S proteasomes, intervenes in cancer progression for anti-endocrine therapy in BCa. Here we report that proteasome-associated deubiquitinases (USP14 and UCHL5) inhibitors b-AP15 and platinum pyrithione (PtPT) induce growth inhibition in ERα+ BCa cells. Further studies show that these inhibitors induce cell cycle arrest and apoptosis associated with caspase activation, endoplasmic reticulum (ER) stress and the downregulation of ERα. Moreover, we suggest that b-AP15 and PtPT block ERα signaling via enhancing the ubiquitin-mediated degradation of ERα and inhibiting the transcription of ERα. Collectively, these findings demonstrate that proteasome-associated deubiquitinases inhibitors b-AP15 and PtPT may have the potential to treat BCa resistant to anti-hormonal therapy.

Highlights

Breast cancer (BCa) is a common malignancy and the second most deadly cancer among women, with an increasing incidence worldwide[1,2]
The effect of b-AP15 and Platinum pyrithione (PtPT) in triple negative breast cancer (TNBC) and endoplasmic reticulum (ER)−/ HER2+ breast cancer were detected through the above assay
We found that b-AP15 and PtPT dose- and time- dependently induced caspase-3 activation, PARP cleavage and BCl-2 downregulation (Fig. 2e, f).These results indicate that b-AP15 and PtPT trigger apoptosis in ER+ BCa cells and this is associated with caspase activation and mitochondria malfunction

Summary

Introduction

Breast cancer (BCa) is a common malignancy and the second most deadly cancer among women, with an increasing incidence worldwide[1,2]. It is well known that roughly 70% of BCa cells express estrogen receptor alpha (ERα) and sex hormones, which are critical to breast carcinogenesis[3,4,5]. A lot of compounds were studied on ER-positive (ER+) breast cancer cells[7,8,9,10]. Despite of these recent advances, some of patients did not respond to the treatment. Identifying alternative strategies is a current challenge and an urgent need for the treatment of BCa

Methods

Results

Conclusion