Cipolletti Manuela, Acconcia Filippo
Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy.
Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy.
Mol Cell Endocrinol. 2024 Apr 15;584:112160. doi: 10.1016/j.mce.2024.112160. Epub 2024 Jan 22.
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 ESR1 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.
乳腺癌（BC）亚型中的代谢重编程提供了潜在的个性化治疗靶点。接受内分泌治疗（ET）的雌激素受体α（ERα）阳性BC患者可能会发展为对ET耐药的转移性疾病。特定突变，如ERα中的Y537S，会驱动细胞不受控制地增殖。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，ERα Y537S突变细胞中会发生代谢重编程。因此，我们进行了一项筛选，以鉴定可降低ERα Y537S细胞内水平并抑制细胞增殖的代谢蛋白。
在基于小干扰RNA的筛选中鉴定出九种代谢蛋白，其中磷酸甘露糖变位酶2（PMM2）最具潜力。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，我们测试了PMM2减少对突变体高活性表型及其与转移性BC治疗药物联合使用时增殖的影响。
PMM2成为一个重要靶点，因为它与更好的无复发生存率相关，在ERα阳性肿瘤中过表达，且在表达ERα Y537S的细胞中升高。PMM2的缺失诱导ERα Y537S的降解，抑制细胞增殖，并降低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的缺失导致ESR1 mRNA水平降低，从而导致ERα受体蛋白表达减少。此外，PMM2的减少会降低FOXA1水平，而FOXA1在ERα调节中起关键作用。
我们的研究结果确定PMM2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。
