组蛋白赖氨酸特异性去甲基酶 1 (LSD1) 在三阴性乳腺癌 (TNBC) 中经常过度表达，这与 TNBC 患者较差的临床结果相关。然而，LSD1 促进 TNBC 进展的潜在机制仍有待确定。我们最近通过将乳腺条件性LSD1敲除小鼠与Brca1缺陷小鼠杂交建立了基因工程小鼠模型，以探讨LSD1在TNBC发病机制中的作用。 Cre介导的Brca1缺失导致小鼠乳腺中肿瘤形成的发生率更高，而同时LSD1的缺失阻碍了肿瘤形成，表明LSD1在促进Brca1缺陷型肿瘤中发挥着关键作用。我们还证明，肿瘤抑制基因组织因子通路抑制剂 2 (TFPI2) 的沉默与 LSD1 介导的 TNBC 进展具有功能相关性。与正常乳腺组织相比，小鼠 Brca1 缺陷肿瘤表现出 LSD1 表达升高和 TFPI2 水平降低。 TCGA 数据库分析显示，侵袭性 ER 阴性或基底样 BC 中 TFPI2 表达显着降低。通过 LSD1 抑制恢复 TFPI2 可增加 TFPI2 启动子处 H3K4me2 的富集，抑制肿瘤进展，并增强化疗药物的抗肿瘤功效。 LSD1 消融诱导 TFPI2 下调基质金属蛋白酶 (MMP) 的活性，进而增加肿瘤环境中细胞毒性 T 淋巴细胞吸引趋化因子的水平，导致 CD8 T 细胞的肿瘤浸润增强。此外，在免疫原性差的 TNBC 中，TFPI2 的诱导增强了 LSD1 抑制剂的抗肿瘤作用和免疫检查点阻断。总之，我们的研究确定了 TFPI2 在 LSD1 介导的 TNBC 进展、治疗反应和免疫原性作用中以前未被认识的作用。版权所有 © 2024。由 Elsevier B.V. 出版。

Histone lysine-specific demethylase 1 (LSD1) is frequently overexpressed in triple negative breast cancer (TNBC), which is associated with worse clinical outcome in TNBC patients. However, the underlying mechanisms by which LSD1 promotes TNBC progression remain to be identified. We recently established a genetically engineered murine model by crossing mammary gland conditional LSD1 knockout mice with Brca1-deficient mice to explore the role of LSD1 in TNBC pathogenesis. Cre-mediated Brca1 loss led to higher incidence of tumor formation in mouse mammary glands, which was hindered by concurrent depletion of LSD1, indicating a critical role of LSD1 in promoting Brca1-deficient tumors. We also demonstrated that the silencing of a tumor suppressor gene, Tissue Factor Pathway Inhibitor 2 (TFPI2), is functionally associated with LSD1-mediated TNBC progression. Mouse Brca1-deficient tumors exhibited elevated LSD1 expression and decreased TFPI2 level compared to normal mammary tissues. Analysis of TCGA database revealed that TFPI2 expression is significantly lower in aggressive ER-negative or basal-like BC. Restoration of TFPI2 through LSD1 inhibition increased H3K4me2 enrichment at the TFPI2 promoter, suppressed tumor progression, and enhanced antitumor efficacy of chemotherapeutic agent. Induction of TFPI2 by LSD1 ablation downregulates activity of matrix metalloproteinases (MMPs) that in turn increases the level of cytotoxic T lymphocyte attracting chemokines in tumor environment, leading to enhanced tumor infiltration of CD8+ T cells. Moreover, induction of TFPI2 potentiates antitumor effect of LSD1 inhibitor and immune checkpoint blockade in poorly immunogenic TNBC. Together, our study identifies previously unrecognized roles of TFPI2 in LSD1-mediated TNBC progression, therapeutic response, and immunogenic effects.Copyright © 2024. Published by Elsevier B.V.