Vitamin D and HA Signaling in TNBC

 描述(申请人提供)：乳腺癌是一种异质性疾病，至少有4种主要的分子定义的亚型。在每年确诊为乳腺癌的20万名妇女中，有15%-25%的人被诊断为“三阴性”乳腺癌(TNBC)，这种癌症缺乏雌激素和孕激素受体，也没有Her2基因的扩增。这些肿瘤通常具有基底样的基因表达特征，代表着最具侵袭性和致命性的疾病亚型，几乎没有治疗选择。在之前的资助期间，我们证明了维生素D的活性形式1，25D显著抑制透明质酸合成酶-2(HAS2)的表达和活性，HAS2基因在TNBC中优先过度表达。重要的是，肿瘤过度表达HAS2的TNBC妇女显著降低了存活率，这表明靶向该基因可能会对疾病进展产生影响。HAS2编码一种产生透明质酸(HA)的酶，透明质酸是一种分泌聚合物，激活细胞表面受体CD44，CD44在功能上与获得“干细胞”或“肿瘤启动细胞”的特性有关。有相当多的证据表明，TNBCs的生存依赖于CD44，但HAS2和HA在这些作用中的作用尚未被研究。该项目将检验TNBCs依赖于HAS2产生的HA来驱动CD44介导的生存信号的假设。我们的初步数据有力地表明，维生素D抑制HAS2活性和HA合成是阻断TNBC细胞中CD44信号的可行方法。这项拟议的研究将考察维生素D和其他三种天然产物(4-甲基伯乐酮[4-MU]、磺基喹诺酮[SQ]和氨基葡萄糖)在体外和体内TNBC模型中对HA代谢和CD44信号的独立和交互作用。如果我们的临床前研究表明，这些药物中的任何一种或所有都对疾病进展有影响，我们建议测量HA代谢的生化指标可能成为识别最有可能对这些干预措施有反应的乳腺癌患者的有用筛查。因此，该项目的完成将提供有关这些制剂在患有TNBC的妇女中的使用情况的重要翻译信息。

 DESCRIPTION (provided by applicant): Breast cancer is a heterogeneous disease with at least 4 major molecularly defined sub-types. Of the >200,000 women diagnosed with breast cancer annually, between 15-25% are diagnosed with "triple negative" breast cancer (TNBC) which lack estrogen and progesterone receptors and do not exhibit amplification of Her2. These tumors usually have basal-like gene expression signatures and represent the most aggressive and lethal subtype of the disease with few treatment options. During the previous funding period we demonstrated that 1,25D, the active form of vitamin D, markedly suppresses the expression and activity of hyaluronan synthase-2 (HAS2), a gene that is preferentially overexpressed in TNBC. Importantly, women with TNBC whose tumors overexpress HAS2 have significantly reduced survival, suggesting that targeting this gene is likely to have an impact on disease progression. HAS2 encodes an enzyme that produces hyaluronic acid (HA) a secreted polymer that activates the cell surface receptor CD44 which has been functionally associated with the acquisition of "stem-cell" or "tumor initiating cell" properties. There is considerable evidence tht TNBCs are dependent on CD44 for survival, but the role of HAS2 and HA in mediating these effects have not been studied. This project will test the hypothesis that TNBCs are dependent on HAS2-generated HA to drive CD44 mediated survival signaling. Our preliminary data strongly suggests that vitamin D suppression of HAS2 activity and HA synthesis represents a feasible approach for interrupting CD44 signaling in TNBC cells. The proposed studies will examine the independent and interactive effects of vitamin D and three other natural products (4-methylumberellifone [4MU], sulfoquinovose [SQ] and glucosamine) on HA metabolism and CD44 signaling in TNBC models in vitro and in vivo. If our pre-clinical studies demonstrate that any or all of these agents impact on disease progression, we propose that measuring biochemical measures of HA metabolism could become a useful screen to identify breast cancer patients who are most likely to respond to these interventions. Completion of this project will thus provide important translational information regarding the use of these agents in women living with TNBC.