乳腺癌是全球女性中最常见的癌症。过度激活的雌激素受体 (ER) α 信号被认为是管腔乳腺癌的主要因素，可以通过选择性雌激素受体调节剂 (SERM)（如他莫昔芬）有效控制。然而，大约 30-40% 的 ER  乳腺癌病例在他莫昔芬治疗后复发。这意味着乳腺癌的治疗仍然受到他莫昔芬耐药性的阻碍。最近的研究表明 ERα 的翻译后修饰在内分泌抵抗中发挥着重要作用。 ERα 蛋白及其转录组的稳定性受 E3 泛素连接酶和去泛素酶之间的平衡调节。根据目前的了解，人类基因组中编码了大约100种去泛素酶，但尚不清楚哪些去泛素酶在雌激素信号传导和内分泌抵抗中发挥关键作用。因此，解码显着影响雌激素信号传导的关键去泛素酶，包括控制 ERα 表达和稳定性，对于改善乳腺癌治疗至关重要。我们使用了几种 ER 阳性乳腺癌细胞系、DUB siRNA 文库筛选、异种移植模型、内分泌耐药（ERα-Y537S）模型，并进行免疫印迹、实时 PCR、RNA 测序、免疫荧光和荧光素酶活性测定，以研究 USP36 在乳腺癌进展和他莫昔芬耐药中的功能。在这项研究中，我们鉴定了泛素特异性肽酶 36 (USP36) 作为一种关键的去泛素酶，参与 ERα 信号传导，并通过去泛素酶 siRNA 库筛选来促进乳腺癌的进展。体外和体内研究表明，USP36（而非其催化失活突变体 (C131A)）可以通过 ERα 信号传导促进乳腺癌进展。相反，沉默 USP36 会抑制肿瘤发生。在内分泌治疗耐药模型中，沉默 USP36 会破坏 ERα (Y537S) 耐药形式的稳定性，并恢复对他莫昔芬的敏感性。分子研究表明，USP36 抑制 ERα 的 K48 连接的多聚泛素化并增强 ERα 转录组。有趣的是，我们的结果表明 USP36 作为治疗乳腺癌的新型生物标志物。我们的研究揭示了抑制 USP36 与他莫昔芬联合可能为乳腺癌提供潜在疗法的可能性。© 2024。作者。

Breast cancer is the most prevalent cancer in women globally. Over-activated estrogen receptor (ER) α signaling is considered the main factor in luminal breast cancers, which can be effectively managed with selective estrogen receptor modulators (SERMs) like tamoxifen. However, approximately 30-40% of ER + breast cancer cases are recurrent after tamoxifen therapy. This implies that the treatment of breast cancer is still hindered by resistance to tamoxifen. Recent studies have suggested that post-translational modifications of ERα play a significant role in endocrine resistance. The stability of both ERα protein and its transcriptome is regulated by a balance between E3 ubiquitin ligases and deubiquitinases. According to the current knowledge, approximately 100 deubiquitinases are encoded in the human genome, but it remains unclear which deubiquitinases play a critical role in estrogen signaling and endocrine resistance. Thus, decoding the key deubiquitinases that significantly impact estrogen signaling, including the control of ERα expression and stability, is critical for the improvement of breast cancer therapeutics.We used several ER positive breast cancer cell lines, DUB siRNA library screening, xenograft models, endocrine-resistant (ERα-Y537S) model and performed immunoblotting, real time PCR, RNA sequencing, immunofluorescence, and luciferase activity assay to investigate the function of USP36 in breast cancer progression and tamoxifen resistance.In this study, we identify Ubiquitin-specific peptidase 36 (USP36) as a key deubiquitinase involved in ERα signaling and the advancement of breast cancer by deubiquitinases siRNA library screening. In vitro and in vivo studies showed that USP36, but not its catalytically inactive mutant (C131A), could promote breast cancer progression through ERα signaling. Conversely, silencing USP36 inhibited tumorigenesis. In models resistant to endocrine therapy, silencing USP36 destabilized the resistant form of ERα (Y537S) and restored sensitivity to tamoxifen. Molecular studies indicated that USP36 inhibited K48-linked polyubiquitination of ERα and enhanced the ERα transcriptome. It is interesting to note that our results suggest USP36 as a novel biomarker for treatment of breast cancer.Our study revealed the possibility that inhibiting USP36 combined with tamoxifen could provide a potential therapy for breast cancer.© 2024. The Author(s).