乳腺癌（BCa）是一种高度异质性的疾病，激素受体状态是患者预后和治疗决策的关键因素。大多数原发性肿瘤的雌激素受体α（ERα）呈阳性，ERα在肿瘤发生和疾病进展中发挥着关键作用，是BCa治疗的主要靶点。然而，大约三分之一的 ERα 阳性 BCa 患者会复发并进展至转移期，其中 20% 的转移病例在内分泌治疗后出现 ERα 表达丧失（称为 ERα 转化）。目前尚不清楚 ERα 转化的癌症在生物学上是否与真正的 ERα 阴性疾病相似，以及哪些信号级联可以补偿 ERα 的损失并驱动肿瘤进展。为了更好地了解 ERα 丢失后转移性 BCa 中发生的生物学变化，我们对 37 名乳腺癌患者的 47 例恶性胸腔积液进行了（磷酸）蛋白质组学分析，比较了 ERα 阳性、ERα 转化和 ERα 阴性病例。我们的数据显示，该转移位点中 ERα 依赖性的丧失仅导致部分转变为 ERα 阴性分子表型，并保留了类似管腔的蛋白质组景观。此外，我们发现了 ERα 转化转移瘤中几种关键激酶活性降低的证据，包括血清/糖皮质激素调节激酶 1 (SGK1)。 SGK1 底物磷酸化的丧失可以补偿晚期疾病中 ERα 依赖性的丧失，并暴露出可用于治疗这些患者的潜在治疗漏洞。本文受版权保护。版权所有。

Breast cancer (BCa) is a highly heterogeneous disease, with hormone receptor status being a key factor in patient prognostication and treatment decision-making. The majority of primary tumours are positive for estrogen receptor alpha (ERα), which plays a key role in tumorigenesis and disease progression, and represents the major target for treatment of BCa. However, around one third of patients with ERα-positive BCa relapse and progress into the metastatic stage, with 20% of metastatic cases characterised by loss of ERα expression after endocrine treatment, known as ERα-conversion. It remains unclear whether ERα-converted cancers are biologically similar to bona fide ERα-negative disease and which signalling cascades compensate for ERα loss and drive tumour progression. To better understand the biological changes that occur in metastatic BCa upon ERα loss, we performed (phospho)proteomics analysis of 47 malignant pleural effusions derived from 37 breast cancer patients, comparing ERα-positive, ERα-converted and ERα-negative cases. Our data revealed that the loss of ERα-dependency in this metastatic site leads to only a partial switch to an ERα-negative molecular phenotype, with preservation of a luminal-like proteomic landscape. Furthermore, we found evidence for decreased activity of several key kinases, including serum/glucocorticoid regulated kinase 1 (SGK1), in ERα-converted metastases. Loss of SGK1 substrate phosphorylation may compensate for the loss of ERα-dependency in advanced disease and exposes a potential therapeutic vulnerability that may be exploited in treating these patients.This article is protected by copyright. All rights reserved.