Background: The progression of tumors from less aggressive subtypes to more aggressive states during metastasis poses challenges for treatment strategies. Previous studies have revealed the molecular subtype conversion between primary and metastatic tumors in breast cancer (BC). However, the subtype conversion during lymph node metastasis (LNM) and the underlying mechanism remains unclear. Methods: We compared clinical subtypes in paired primary tumors and positive lymph nodes (PLNs) in BC patients and further validated them in the mouse model. Bioinformatics analysis and macrophage-conditioned medium treatment were performed to investigate the role of macrophages in subtype conversion. Results: During LNM, hormone receptors (HRs) were down-regulated, while HER2 was up-regulated, leading to the transformation of luminal A tumors towards luminal B tumors and from luminal B subtype towards HER2-enriched (HER2-E) subtype. The mouse model demonstrated the elevated levels of HER2 in PLN while retaining luminal characteristics. Among the various cells in the tumor microenvironment (TME), macrophages were the most clinically relevant in terms of prognosis. The treatment of a macrophage-conditioned medium further confirmed the downregulation of HR expression and upregulation of HER2 expression, inducing tamoxifen resistance. Through bioinformatics analysis, MNX1 was identified as a potential transcription factor governing the expression of HR and HER2. Conclusion: Our study revealed the HER2-E subtype conversion during LNM in BC. Macrophages were the crucial cell type in TME, inducing the downregulation of HR and upregulation of HER2, probably via MNX1. Targeting macrophages or MNX1 may provide new avenues for endocrine therapy and targeted treatment of BC patients with LNM.
背景：肿瘤在转移过程中由侵袭性较低的亚型向侵袭性更强的状态进展，对治疗策略提出了挑战。既往研究已揭示乳腺癌原发灶与转移灶之间的分子亚型转换现象，但淋巴结转移过程中的亚型转换及其潜在机制尚不明确。方法：我们比较了乳腺癌患者配对原发灶与阳性淋巴结的临床亚型，并在小鼠模型中进一步验证。通过生物信息学分析和巨噬细胞条件培养基处理，探究巨噬细胞在亚型转换中的作用。结果：淋巴结转移过程中激素受体表达下调，HER2表达上调，导致管腔A型肿瘤向管腔B型转化，管腔B型向HER2富集型转化。小鼠模型证实阳性淋巴结中HER2水平升高，同时保留管腔特征。在肿瘤微环境各类细胞中，巨噬细胞与患者预后的临床相关性最为显著。巨噬细胞条件培养基处理进一步证实其可下调激素受体表达、上调HER2表达，并诱导他莫昔芬耐药。生物信息学分析发现MNX1可能是调控激素受体和HER2表达的潜在转录因子。结论：本研究揭示了乳腺癌淋巴结转移过程中的HER2富集型亚型转换现象。巨噬细胞作为肿瘤微环境中的关键细胞类型，可能通过MNX1介导激素受体下调和HER2上调。靶向巨噬细胞或MNX1可能为伴有淋巴结转移的乳腺癌患者的内分泌治疗和靶向治疗提供新途径。
Macrophages Promote Subtype Conversion and Endocrine Resistance in Breast Cancer
肿瘤(癌症)患者之家