Metabolic reprogramming in breast cancer (BC) subtypes offers potential personalized treatment targets. Estrogen receptor α (ERα)-positive BC patients undergoing endocrine therapy (ET) can develop ET-resistant metastatic disease. Specific mutations, like Y537S in ERα, drive uncontrolled cell proliferation. Targeting mutant receptor levels shows promise for inhibiting growth in metastatic BC expressing ERα variants. Additionally, metabolic reprogramming occurs in ERα Y537S mutant cells. Consequently, we conducted a screen to identify metabolic proteins reducing intracellular levels of ERα Y537S and inhibiting cell proliferation. Nine metabolic proteins were identified in a siRNA-based screen, with phosphomannose mutase 2 (PMM2) showing the most promise. We measured the impact of PMM2 depletion on ERα stability and cell proliferation in ERα Y537S mutant cells. Additionally, we tested the effect of PMM2 reduction on the hyperactive phenotype of the mutant and its proliferation when combined with metastatic BC treatment drugs. PMM2 emerged as a significant target due to its correlation with better relapse-free survival, overexpression in ERα-positive tumors, and its elevation in ERα Y537S-expressing cells. Depletion of PMM2 induces degradation of ERα Y537S, inhibits cell proliferation, and reduces ERα signaling. Notably, reducing PMM2 levels re-sensitizes ERα Y537S-expressing cells to certain ET drugs and CDK4/CDK6 inhibitors. Mechanistically, depletion of PMM2 leads to a reduction in mRNA levels, resulting in decreased ERα receptor protein expression. Furthermore, the reduction of PMM2 decreases FOXA1 levels, which plays a crucial role in ERα regulation. Our findings establish PMM2 as an innovative therapeutic target for metastatic BC expressing the ERα Y537S variant, offering alternative strategies for managing and treating this disease.

中文翻译：

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PMM2 控制表达 ESR1 Y537S 变体的乳腺癌细胞中的 ERα 水平和细胞增殖

乳腺癌（BC）亚型的代谢重编程提供了潜在的个性化治疗目标。接受内分泌治疗 (ET) 的雌激素受体 α (ERα) 阳性 BC 患者可能会出现 ET 耐药性转移性疾病。 ERα 中的 Y537S 等特定突变会导致不受控制的细胞增殖。靶向突变受体水平有望抑制表达 ERα 变体的转移性 BC 的生长。此外，代谢重编程发生在 ERα Y537S 突变细胞中。因此，我们进行了筛选，以确定降低细胞内 ERα Y537S 水平并抑制细胞增殖的代谢蛋白。基于 siRNA 的筛选鉴定出九种代谢蛋白，其中磷酸甘露糖变位酶 2 (PMM2) 最有希望。我们测量了 PMM2 缺失对 ERα Y537S 突变细胞中 ERα 稳定性和细胞增殖的影响。此外，我们还测试了与转移性 BC 治疗药物联合使用时 PMM2 减少对突变体过度活跃表型及其增殖的影响。 PMM2 成为一个重要的靶点，因为它与更好的无复发生存、ERα 阳性肿瘤中的过度表达以及 ERα Y537S 表达细胞中的表达升高相关。 PMM2 的耗竭会诱导 ERα Y537S 降解，抑制细胞增殖，并减少 ERα 信号传导。值得注意的是，降低 PMM2 水平可使表达 ERα Y537S 的细胞对某些 ET 药物和 CDK4/CDK6 抑制剂重新敏感。从机制上讲，PMM2 的消耗会导致 mRNA 水平降低，从而导致 ERα 受体蛋白表达降低。此外，PMM2 的减少会降低 FOXA1 水平，而 FOXA1 在 ERα 调节中起着至关重要的作用。我们的研究结果确立了 PMM2 作为表达 ERα Y537S 变体的转移性 BC 的创新治疗靶点，为管理和治疗这种疾病提供了替代策略。