侵袭性的雌激素受体（ER）阳性乳腺癌通常对他莫昔芬产生耐药性;替代激素治疗方法可用于治疗，但对于预防，特别是在绝经前的女性中则没有。我们研究了选择性ER调节剂（Z-内酰胺）作为单独治疗及与选择性孕激素受体调节剂（奥那普利斯通和尤利普利司酸酯）联合应用于他莫昔芬不敏感的C3（1）/ SV40TAg小鼠乳腺肿瘤形成模型的疗效。与人等剂量（HED）101mg/天的他莫昔芬相比，HED 24mg/天的内酰胺显著增加了潜伏期并减少了肿瘤生长。HED 81mg/天的尤利普利司酸酯也显著增加了潜伏期，但未能抑制肿瘤生长，而HED 98mg/天的奥那普利斯通在这个模型中没有肿瘤预防效果。将尤利普利司酸酯添加到内酰胺中并不能提高预防效果。内酰胺和尤利普利司酸酯同样抑制与细胞周期，细胞增殖和细胞外基质重塑相关的基因表达，但仅内酰胺显著下调与预后不良相关的显著基因（Col11a1，Il17b, Pdgfa，Tnfrsf11a）。我们的结果表明，内酰胺可以通过有利的组织重塑和免疫调节发挥预防乳腺癌的作用，即使是对于对他莫昔芬产生耐药性的癌症也是如此。版权所有©2023 Elsevier Masson SAS出版。

Aggressive estrogen receptor (ER) positive breast cancer is frequently tamoxifen-resistant; alternative endocrine approaches exist for therapy, but not for prevention, particularly in premenopausal women. We examined the efficacy of the selective ER modulator (Z-endoxifen) as monotherapy and in combination with the selective progesterone receptor modulators (onapristone and ulipristal acetate) in the tamoxifen-insensitive C3(1)/SV40TAg mouse mammary tumorigenesis model. Unlike tamoxifen at human equivalent dose (HED) 101 mg/day, endoxifen at HED 24 mg/day significantly increased latency and reduced tumor growth relative to untreated controls. Ulipristal acetate (UPA) at HED 81 mg/day also significantly increased latency however failed to inhibit tumor growth, while onapristone (HED 98 mg/day) had no tumor prevention efficacy in this model. Addition of UPA to endoxifen did not enhance preventive efficacy over endoxifen alone. The expression of genes associated with cell cycle, cell proliferation and extracellular matrix remodeling was similarly repressed by endoxifen and UPA however only endoxifen significantly downregulated prominent genes associated with poor prognosis (Col11a1, Il17b, Pdgfa, Tnfrsf11a). Our results indicate that endoxifen can prevent breast cancers, even when tamoxifen-resistant, through its role in favorable tissue remodeling and immunomodulation.Copyright © 2023. Published by Elsevier Masson SAS.