Chemoprevention of breast cancer with rexinoids that inhibit obesity-induced metabolic syndrome

 描述（由申请人提供）：乳腺癌的终生风险范围从一般人群的约12%到高危女性（如BRCA突变携带者）的65%以上，强调了安全有效的化学预防的必要性。目前批准的药物，他莫昔芬和雷洛昔芬，只能预防ER阳性（ER+）乳腺肿瘤。因此，ER阴性（ER-）癌症的预防仍然是一个重大挑战。RXR核受体的类Rexinoid激动剂，如Targretin，在动物化学预防模型中预防ER+和ER-癌症;但它们诱导严重的高脂血症，这限制了它们的使用。使用基于结构的药物设计，我们开发了一组结构独特的rexinoids，III类UAB rexinoids（以UAB 125和UAB 126为例），在ER小鼠模型中具有有效的化学预防功效。然而，这些III类rexinoids在化学预防性rexinoids中是独特的，因为它们实际上降低而不是升高治疗动物的血清脂质水平。此外，我们的初步数据表明，UAB 126可以预防饮食诱导的肥胖和代谢综合征，这两者都会增加患乳腺癌的风险。因此，我们假设（1）III类rexinoids可以抵消高脂饮食和肥胖的促肿瘤作用;（2）这些rexinoids的代谢作用可能部分通过直接影响正常和/或（前）恶性乳腺上皮细胞的代谢稳态来介导其化学预防活性。为了解决这些概念，将在ER-小鼠模型中通过评估在正常或高脂饮食（HFD）喂养的动物之间类瑞昔肽诱导的肿瘤数量、肿瘤质量和肿瘤发生时间的差异来评价化学预防活性。这些研究将揭示III类rexinoids在HFD环境中的化学预防功效。rexinoid化学预防的分子机制将通过三管齐下的方法来解决：（1）使用RNAseq来评估不同组织中由HFD和/或III类rexinoid治疗诱导的基因表达模式（乳腺肿瘤、正常乳腺组织、脂肪细胞），其将鉴定类瑞昔康作用的潜在途径;（2）使用等温量热法评估类瑞昔康诱导的选择共调节剂的稳定性：受体复合物，这将定义这些类Rexinoids作为不同RXR异二聚体的激动剂/拮抗剂的特定作用;和（3）使用siRNA筛选来鉴定与III类Rexinoids的化学预防作用功能相关的基因和途径。这些发现的整合将为 肥胖、代谢综合征与乳腺癌发生和发展之间因果关系的未来研究。

 DESCRIPTION (provided by applicant): The life-long risk of breast cancer ranges from ~12% in the general population, to over 65% in high-risk women (such as BRCA mutant carriers), emphasizing the need for safe and effective chemoprevention. Currently approved drugs, tamoxifen and raloxifene, prevent only ER-positive (ER+) breast tumors. Thus, the prevention of ER-negative (ER-) cancers remains a major challenge. Rexinoid agonists of RXR nuclear receptors, such as Targretin, prevent both ER+ and ER-cancers in animal chemoprevention models; but they induce severe hyperlipidemia, which limits their use. Using structure-based drug design, we developed a structurally unique group of rexinoids, Class III UAB rexinoids (exemplified by UAB125 andUAB126), with potent chemopreventive efficacy in an ER-mouse model. However, these Class III rexinoids are unique among chemopreventive rexinoids in that they actually lower, rather than elevate, serum lipid levels in treated animals. Moreover, our preliminary data suggest that UAB126 prevents diet-induced obesity and metabolic syndrome, both of which increase the risk of developing breast cancer. Thus, we hypothesize that (1) Class III rexinoids can counteract the tumor-promoting effects of high-fat diet and obesity; and (2) the metabolic actions of these rexinoids may, in part, mediate their chemopreventive activity by directly affecting the metabolic homeostasis of normal and/or (pre)malignant mammary epithelial cells. To address these concepts, chemopreventive activity will be evaluated in an ER-mouse model by assessing rexinoid-induced differences in tumor number, tumor mass, and time to tumor occurrence between animals fed normal or high-fat diet (HFD). These studies will reveal the chemopreventive efficacy of Class III rexinoids in a HFD setting. The molecular mechanisms of rexinoid chemoprevention will be addressed with a three-prong approach: (1) using RNAseq to assess gene expression patterns induced by HFD and/or treatment with Class III rexinoids in distinct tissues (mammary tumors, normal mammary tissue, adipocytes), which will identify potential pathways of rexinoid action; (2) using Isothermal calorimetry to assess rexinoid-induced stabilization of select co-regulator:receptor complexes, which will define specific roles of these rexinoids as agonists/antagonists of distinct RXR heterodimers; and (3) using siRNA screening to identify genes and pathways functionally relevant for the chemopreventive action of Class III rexinoids. Integration of these findings will lay the basis for future studies of the causal links between obesity, metabolic syndrome, and initiation and progression of breast cancer.