Bariatric surgery is associated with improved outcomes for several cancers, including breast cancer (BC), although the mechanisms mediating this protection are unknown. We hypothesized that elevated bile acid pools detected after bariatric surgery may be factors that contribute to improved BC outcomes. Patients with greater expression of the bile acid receptor FXR displayed improved survival in specific aggressive BC subtypes. FXR is a nuclear hormone receptor activated by primary bile acids. Therefore, we posited that activating FXR using an established FDA-approved agonist would induce anticancer effects. Using in vivo and in vitro approaches, we determined the anti-tumor potential of bile acid receptor agonism. Indeed, FXR agonism by the bile acid mimetic known commercially as Ocaliva (“OCA”), or Obeticholic acid (INT-747), significantly reduced BC progression and overall tumor burden in a pre-clinical model. The transcriptomic analysis of tumors in mice subjected to OCA treatment revealed differential gene expression patterns compared to vehicle controls. Notably, there was a significant down-regulation of the oncogenic transcription factor MAX (MYC-associated factor X), which interacts with the oncogene MYC. Gene set enrichment analysis (GSEA) further demonstrated a statistically significant downregulation of the Hallmark MYC-related gene set (MYC Target V1) following OCA treatment. In human and murine BC analyses in vitro, agonism of FXR significantly and dose-dependently inhibited proliferation, migration, and viability. In contrast, the synthetic agonism of another common bile acid receptor, the G protein-coupled bile acid receptor TGR5 (GPBAR1) which is mainly activated by secondary bile acids, failed to significantly alter cancer cell dynamics. In conclusion, agonism of FXR by primary bile acid memetic OCA yields potent anti-tumor effects potentially through inhibition of proliferation and migration and reduced cell viability. These findings suggest that FXR is a tumor suppressor gene with a high potential for use in personalized therapeutic strategies for individuals with BC.
减重手术与包括乳腺癌在内的多种癌症预后改善相关，但其保护机制尚不明确。我们推测减重术后检测到的胆汁酸池升高可能是改善乳腺癌预后的关键因素。在特定侵袭性乳腺癌亚型中，胆汁酸受体FXR高表达患者显示出更好的生存率。FXR是一种由初级胆汁酸激活的核激素受体。因此我们提出假设：使用已获FDA批准的激动剂激活FXR可诱导抗癌效应。通过体内外实验，我们验证了胆汁酸受体激动剂的抗肿瘤潜力。在临床前模型中，胆汁酸模拟物奥贝胆酸（商品名Ocaliva，研发代号INT-747）对FXR的激动作用显著抑制了乳腺癌进展并降低总体肿瘤负荷。对OCA治疗组小鼠肿瘤的转录组学分析显示，与对照组相比其基因表达谱发生显著改变，尤其致癌转录因子MAX（MYC相关因子X）出现显著下调，该因子可与致癌基因MYC相互作用。基因集富集分析进一步证实OCA治疗后，Hallmark MYC相关基因集（MYC靶标V1）出现统计学显著下调。在人类和小鼠乳腺癌体外实验中，FXR激动剂以剂量依赖方式显著抑制肿瘤细胞的增殖、迁移和活力。与此形成对比的是，另一种常见胆汁酸受体TGR5（GPBAR1，主要由次级胆汁酸激活的G蛋白偶联受体）的合成激动剂未能显著改变癌细胞动力学。综上所述，初级胆汁酸模拟物OCA通过激活FXR产生强效抗肿瘤作用，其机制可能涉及抑制增殖迁移及降低细胞活力。这些发现表明FXR作为抑癌基因，在乳腺癌个体化治疗策略中具有重要应用潜力。
FXR Agonism with Bile Acid Mimetic Reduces Pre-Clinical Triple-Negative Breast Cancer Burden
肿瘤(癌症)患者之家