Pharmacological approaches to breast cancer risk-reduction for BRCA1 mutation carriers would provide an alternative to mastectomy. BRCA1-deficiency dysregulates progesterone signaling, promoting tumorigenesis. Selective progesterone receptor (PR) modulators (SPRMs) are therefore candidate prevention agents. However, their efficacy varies in different BRCA1-deficient mouse models. We examined chemopreventive efficacy of telapristone acetate (TPA), ulipristal acetate (UPA) and mifepristone (MFP) in mice with a conditional knockout of the Brca1 C-terminal domain. The SPRMs displayed a spectrum of efficacy: UPA was most effective, TPA less, and MFP ineffective. Compared to no-treatment controls, UPA reduced tumorigenesis (p = 0.04), and increased tumor latency (p = 0.03). In benign mammary glands, UPA decreased Ki67 (p < 0.001) and increased PR expression (p < 0.0001). RNA sequencing analysis revealed distinct gene expression in response to UPA and MFP. UPA downregulated glycolysis and extracellular matrix-inflammation genes (Fn1, Ptgs2, Tgfb2, Tgfb3) whereas MFP downregulated claudin genes and upregulated amino acid metabolism and inflammation genes. The anti-glucocorticoid effects of MFP appeared not to be tumor-protective, while altering estrogen receptor signaling and NF-kB activation. Our study points to an important role of epithelial PR and its paracrine action on the microenvironment in BRCA1-deficient mammary tumorigenesis, and prevention.

降低BRCA1突变携带者患乳腺癌风险的药理学方法将提供乳房切除术的替代方法。BRCA1 缺乏会失调孕酮信号传导，促进肿瘤发生。因此，选择性孕酮受体 (PR) 调节剂 (SPRM) 是候选预防剂。然而，它们的功效在不同的 BRCA1 缺陷小鼠模型中有所不同。我们检查telapristone乙酸的化学预防功效（TPA），醋酸ulipristal（UPA）和米非司酮（MFP）中的小鼠与的条件性敲除BRCA1基因C端域。SPRM 显示出一系列功效：UPA 最有效，TPA 较少，MFP 无效。与未治疗的对照组相比，UPA 减少了肿瘤发生（p = 0.04），并增加了肿瘤潜伏期（p = 0.03）。在良性乳腺中，UPA 降低 Ki67 (p < 0.001) 并增加 PR 表达 (p < 0.0001)。RNA 测序分析揭示了响应 UPA 和 MFP 的不同基因表达。UPA 下调糖酵解和细胞外基质炎症基因（Fn1、Ptgs2、Tgfb2、Tgfb3) 而 MFP 下调 claudin 基因并上调氨基酸代谢和炎症基因。MFP 的抗糖皮质激素作用似乎没有肿瘤保护作用，但会改变雌激素受体信号传导和 NF-kB 活化。我们的研究指出了上皮 PR 及其旁分泌作用在 BRCA1 缺陷型乳腺肿瘤发生和预防中对微环境的重要作用。