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.