抗雌激素药物他莫昔芬是治疗雌激素受体阳性（HR+）乳腺癌患者的高效激素疗法，然而，雌激素受体阴性、孕激素受体阳性（ER-/PR+）亚型无法获得他莫昔芬的益处。因此，ER-/PR+乳腺癌患者的临床结局较差，对于ER-/PR+ 乳腺癌的新型药物治疗对这些患者有益。通过乳腺癌基因表达矿工，在4319名乳腺癌患者样本中对53,805个基因表达进行了HR+乳腺癌和三阴性乳腺癌（TNBC）的分析。从包含1190名人类乳腺癌患者样本的PrognoScan数据库中获得了包括总体生存率、远处转移无病生存率和复发无病生存率在内的临床结局。我们使用CRISPR-Cas9系统或基因敲降（KD）系统，以确定ERα和炎症相关基因（如USP1、CDC20和CASP1）的功能。为了检查ERα KO乳腺癌细胞系的肿瘤细胞增殖和迁移，我们使用了他莫昔芬和炎症抑制剂Ac-YVAD-CHO。为了进一步确认，在使用三维（3D）器官样组织培养系统（体外）中检查了ERα KO乳腺癌细胞系中的癌症生长。我们发现，在4319名乳腺癌患者数据库中，ER-/PR+激素受体阳性乳腺癌的基因表达与ER-/PR-非常相似，而不是其他HR+乳腺癌。特别是，与TNBC高度表达的炎症相关基因USP1、CDC20和CASP1在ER-/PR+ HR+乳腺癌中也被上调。抑制USP1、CDC20和CASP1在ERα KO （ER-/PR+）细胞系中抑制了肿瘤细胞的生长和转移。有趣的是，在HR+细胞系中，ERα的缺失对他莫昔芬不敏感，但对炎症抑制剂Ac-YVAD-CHO非常敏感。在体外和体内（3D器官样培养）模型中，炎症抑制剂可特异性地阻断ER-/PR+肿瘤的增殖和迁移。这些发现表明，炎症抑制剂可能是一种潜在的ER-/PR+ HR乳腺癌患者治疗选项。 © 2023，作者授权给日本乳腺癌学会。

The anti-estrogen tamoxifen is a highly effective hormonal therapy for hormonal-positive (HR+) breast cancer patients; however, the estrogen receptor-negative, progesterone receptor-positive (ER-/PR+) subtype does not give the benefits of tamoxifen. Therefore ER-/PR+ breast cancer has a poor clinical outcome, and novel drug therapy for ER-/PR+ breast cancer could benefit these patients.53,805 gene expressions were characterized into HR+ BC and triple-negative breast cancer (TNBC) and analyzed through Breast Cancer Gene Expression Miner in 4319 breast cancer patient samples. The clinical outcomes including overall survival, distant metastasis-free survival, and relapse-free survival were obtained from the PrognoScan database containing 1190 human breast cancer patient samples. To determine the function of ERα and inflammation-related genes such as USP1, CDC20, and CASP1, we used the CRISPR-Cas9 system or gene knockdown (KD) system. To check tumor cell proliferation and migration of ERα KO breast cancer cell line, we used tamoxifen and the inflammation inhibitor Ac-YVAD-CHO. For further confirmation, cancer growth was checked with the inflammation inhibitor in ERα KO breast cancer cell line using a three-dimensional (3D) organoid tissue culture system (ex vivo).We found that gene expression in ER-/PR+ hormonal-positive breast cancer is positively related to ER-/PR- very similar to TNBC, not other HR+ breast cancer using a 4319 breast cancer patient database. Especially, inflammation-related genes, USP1, CDC20, and CASP1, which are highly expressed in TNBC, are also upregulated in ER-/PR+ HR+ breast cancer. Suppression of USP1, CDC20, and CASP1 inhibited tumor cell growth and metastasis in ERα KO (ER-/PR +) cell lines. Interestingly, loss of ERα in HR+ cell lines is not responsive to tamoxifen, but highly sensitive to the inflammation inhibitor, Ac-YVAD-CHO. In in vitro and ex vivo (3D organoid) models, inflammation inhibitor-specific blocks ER-/PR+ tumor proliferation and migration.These findings suggest that an inflammation inhibitor might be a potential option for therapy for ER-/PR+ HR breast cancer patients.© 2023. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.