It has been well known that androgen receptor (AR) is critical to prostate cancer development and progression. It has also been documented that AR is expressed in more than 60% of breast tumors, which promotes the growth of estrogen receptor-negative (ER^-)/AR-positive (AR⁺) breast cancer cells. Thus, AR might be a potential therapeutic target for AR-positive/ER-negative breast cancer patients. Previously we reported that in prostate cancer cells proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14) stabilized AR protein level by removing its ubiquitin chain. In the current study, we studied the USP14-AR protein interaction and cell proliferation status after USP14 reduction or inhibition in breast cancer cells, and our results support the conclusion that targeting USP14 is a novel strategy for treating AR-responsive breast cancer. We found that inhibition of USP14 accelerated the K48-ubiquitination and proteasome-mediated degradation of AR protein. Additionally, both genetic and pharmacological inhibition of USP14 significantly suppressed cell proliferation in AR-responsive breast cancer cells by blocking G₀/G₁ to S phase transition and inducing apoptosis. Moreover, AR overexpression inhibited USP14 inhibition-induced events, suggesting that AR deubiquitination by USP14 is critical for breast cancer growth and USP14 inhibition is a possible strategy to treat AR-positive breast cancer.

中文翻译：

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通过抑制 USP14 介导的雄激素受体去泛素化，诱导雄激素受体阳性人乳腺癌细胞生长停滞和凋亡。

众所周知，雄激素受体（AR）对于前列腺癌的发生和进展至关重要。还有文献记载，AR在60%以上的乳腺肿瘤中表达，它促进雌激素受体阴性（ER ^-）/AR阳性（AR ⁺）乳腺癌细胞的生长。因此，AR可能是AR阳性/ER阴性乳腺癌患者的潜在治疗靶点。之前我们报道过，在前列腺癌细胞中，蛋白酶体相关的去泛素酶泛素特异性蛋白酶 14 (USP14) 通过去除其泛素链来稳定 AR 蛋白水平。在目前的研究中，我们研究了乳腺癌细胞中USP14减少或抑制后的USP14-AR蛋白相互作用和细胞增殖状态，我们的结果支持这样的结论：靶向USP14是治疗AR反应性乳腺癌的一种新策略。我们发现 USP14 的抑制加速了 AR 蛋白的 K48 泛素化和蛋白酶体介导的降解。_{此外，USP14 的遗传和药理学抑制通过阻断 G 0} /G ₁到 S 相转变并诱导细胞凋亡，显着抑制 AR 反应性乳腺癌细胞的细胞增殖。此外，AR过表达抑制了USP14抑制诱导的事件，表明USP14引起的AR去泛素化对于乳腺癌生长至关重要，并且USP14抑制是治疗AR阳性乳腺癌的一种可能策略。