Targeting Proteasome-Associated Deubiquitinases As a Novel Strategy for the Treatment of Estrogen Receptor-Positive Breast Cancer

Estrogen receptor alpha (ER alpha) is expressed in similar to 67% of breast cancers and is critical to their proliferation and progression. The expression of ER alpha 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 ER alpha(+) 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 ER alpha(+) 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 ER alpha. Moreover, we suggest that b-AP15 and PtPT block ER alpha signaling via enhancing the ubiquitin-mediated degradation of ER alpha and inhibiting the transcription of ER alpha. 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.