Little is known about the role of epithelial membrane protein-2 (EMP2) in breast cancer development or progression. In this study, we tested the hypothesis that EMP2 may regulate the formation or self-renewal of breast cancer stem cells (BCSC) in the tumor microenvironment. In silico analysis of gene expression data demonstrated a correlation of EMP2 expression with known metastasis-related genes and markers of cancer stem cells (CSC) including aldehyde dehydrogenase (ALDH). In breast cancer cell lines, EMP2 overexpression increased and EMP2 knockdown decreased the proportion of stem-like cells as assessed by the expression of the CSC markers CD44+/CD24−, ALDH activity, or by tumor sphere formation. In vivo, upregulation of EMP2 promoted tumor growth, whereas knockdown reduced the ALDHhigh CSC population as well as retarded tumor growth. Mechanistically, EMP2 functionally regulated the response to hypoxia through the upregulation of HIF-1α, a transcription factor previously shown to regulate the self-renewal of ALDHhigh CSCs. Furthermore, in syngeneic mouse models and primary human tumor xenografts, mAbs directed against EMP2 effectively targeted CSCs, reducing the ALDH+ population and blocking their tumor-initiating capacity when implanted into secondary untreated mice. Collectively, our results show that EMP2 increases the proportion of tumor-initiating cells, providing a rationale for the continued development of EMP2-targeting agents.

中文翻译：

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EMP2是乳腺癌细胞干性的新型调节因子


关于上皮膜蛋白 2 (EMP2) 在乳腺癌发生或进展中的作用知之甚少。在这项研究中，我们测试了 EMP2 可能调节肿瘤微环境中乳腺癌干细胞 (BCSC) 的形成或自我更新的假设。基因表达数据的计算机分析证明了 EMP2 表达与已知的转移相关基因和癌症干细胞 (CSC) 标记物（包括乙醛脱氢酶 (ALDH)）的相关性。在乳腺癌细胞系中，通过 CSC 标记物 CD44+/CD24− 的表达、ALDH 活性或肿瘤球形成来评估，EMP2 过表达增加，而 EMP2 敲低则降低了干细胞样细胞的比例。在体内，EMP2 的上调促进肿瘤生长，而敲除则减少 ALDHhigh CSC 群体并延缓肿瘤生长。从机制上讲，EMP2 通过上调 HIF-1α 来功能性调节对缺氧的反应，HIF-1α 是一种转录因子，之前显示可以调节 ALDHhigh CSC 的自我更新。此外，在同基因小鼠模型和原发性人类肿瘤异种移植物中，针对 EMP2 的单克隆抗体可有效靶向 CSC，减少 ALDH+ 数量，并在植入二级未治疗小鼠时阻断其肿瘤启动能力。总的来说，我们的结果表明 EMP2 增加了肿瘤起始细胞的比例，为持续开发 EMP2 靶向药物提供了理论依据。