The role of bile acids to ameliorate obesity driven triple negative breast cancer

三阴性乳腺癌(TNBC)是一种侵袭性亚型，与肥胖相关，不成比例地 影响年轻和少数族裔妇女；由于没有针对这一亚型的分子靶向治疗，结果仍然存在 非常穷。肥胖导致肿瘤微环境的免疫和代谢变化，从而导致 侵袭、转移和复发的风险，以及对治疗反应差和较高的死亡率。尽管 已知的关联，肥胖和乳腺癌之间的机械性相互依存关系仍不清楚。 接受减肥手术的患者患乳腺癌的风险显著降低，包括TNBC。我的 前提是唯一与手术诱导的减肥相关的潜在有益机制可以 被利用来模仿手术的好处，以降低癌症风险。因此，这样做的最终目的是 建议测试新的药物治疗方法，以改善通过饮食和手术获得的TNBC结果 干预措施。手术后体重减轻的一个潜在的中介因素是循环胆汁酸的高度升高。 胆汁酸受体法尼醇X受体(FXR)介导的减肥和代谢益处 做手术。我们提供了引人注目的初步数据，表明FXR激活在体内抑制TNBC进展中的作用 免疫细胞的显著变化表明抗肿瘤免疫能力有所提高。我们还演示了FXR 激活抑制体外培养的人和小鼠TNBC细胞的增殖、迁移和侵袭。在病人身上，我们 观察到FXR是TNBC无复发生存率的重要预测因子。因此，我假设 通过减肥手术后继发的胆汁酸升高或药物靶向FXR激活FXR，将 改善TNBC结果。凭借我的培训和我的指导团队的专业知识，我已经准备好严格地 研究潜在的胆汁酸，FXR，，TNBC机制，以确定FXR激动剂的治疗效果。 目标1将使用临床前TNBC模型来确定胆汁酸升高在多大程度上消除肥胖- 使用创新的胆汁分流减肥手术的相关TNBC进展。目标2将决定是否 使用FDA批准的现有FXR激动剂的药理学FXR激活将提高对 TNBC。使用功能丧失模型Aim 2将确定FXR在肿瘤内在与外在中的作用 抗肿瘤免疫介导的降低TNBC的机制。这项提案的结果将产生很大影响，因为 首次测试了TNBC对胆汁酸和FXR的依赖性。对机械连杆的有限理解 乳腺癌和肥胖症之间的关系是帮助患者的根本障碍。因为肥胖率是 随着这个项目的完成，最终也将解决TNBC治疗中未得到满足的迫切临床需求 AS提供了一个特殊的F32培训机会。

Triple negative breast cancer (TNBC) is an aggressive subtype, associated with obesity, that disproportionately affects young and minority women; with no molecularly targeted therapies for this subtype, outcomes remain very poor. Obesity induces immune and metabolic changes to the tumor microenvironment that lead to higher risk of invasion, metastases, and recurrence, as well as poor response to therapy and higher mortality. Despite known associations, the mechanistic interdependencies between obesity and breast cancer remain unclear. Patients who underwent bariatric surgery had significantly reduced risk of breast cancer, including TNBC. My premise is that underlying beneficial mechanisms uniquely associated with surgically induced weight loss can be capitalized upon to mimic the benefits of surgery to reduce cancer risk. Therefore, the ultimate goal of this proposal is to test novel pharmacologic treatments to improve TNBC outcomes informed by diet and surgical interventions. A potential mediator of benefits after surgical weight loss is highly elevated circulating bile acids. The bile acid receptor, farnesoid X receptor (FXR), mediated weight loss and metabolic benefits of bariatric surgery. We present striking preliminary data for a role of FXR activation in reducing TNBC progression in vivo with significant changes in immune cells suggesting improved anti-tumor immunity. We also demonstrate FXR activation blunts proliferation, migration and invasion in human and murine TNBC cells in vitro. In patients, we observed that FXR is a significant predictor of relapse-free survival in TNBC. Therefore, I hypothesize that activating FXR, via elevated bile acids secondary to bariatric surgery or pharmacologically targeting FXR, will improve TNBC outcomes. With my training and expertise of my mentoring team, I am well poised to rigorously investigate underlying bile acidFXRTNBC mechanisms to determine therapeutic efficacy of FXR agonism. Aim 1 will use a preclinical TNBC model to determine to what extent elevated bile acids abrogate obesity- associated TNBC progression using an innovative bile diversion bariatric surgery. Aim 2 will determine if pharmacologic FXR activation using an existing FDA-approved FXR agonist will improve therapeutic efficacy for TNBC. Using loss of function models Aim 2 will determine the contribution of FXR in tumor intrinsic vs. extrinsic anti-tumor immune-mediated mechanisms to reduce TNBC. Outcomes from this proposal will be high impact as the first to test the dependence of TNBC on bile acids and FXR. A limited understanding of the mechanistic links between breast cancer and obesity pose a fundamental obstacle to helping patients. Since obesity rates are rising, completion of this project will ultimately address an urgent unmet clinical need in TNBC treatment as well as provide an exceptional F32 training opportunity.