Transcriptional regulation of tumor growth

描述（由申请人提供）： 乳腺癌（BC）仍然是女性最常见的癌症，每年造成近40，000人死亡。根据退伍军人事务部妇女退伍军人中心的数据，妇女是美国退伍军人中增长最快的群体，预计这一数字将在未来10年内增长。因此，随着人口老龄化，退伍军人管理局的医疗保健将是妇女退伍军人的高需求。这是因为在VA人群中也发现了一些与一般人群中预后不良相关的相同风险因素。VA还治疗了中等高量的男性BC，与女性BC的死亡率下降不同，男性BC的死亡率并未下降。与一般人群相比，VA系统中的男性和女性BC患者中非洲裔美国人的比例较高，相对于私营部门，这一人群的死亡率和发病率较高。因此，确定有效的 治疗这些不同退伍军人群体的治疗目标与退伍军人事务部的病人护理使命高度相关。 之前VA Merit资助的项目解决了有关乳腺癌如何获得激素独立性并转移或扩散到全身的问题。我们怀疑这种类型的肿瘤进展是由BC蛋白（RUNX2）控制的，该蛋白调节促进生长和转移的基因的表达。我们还建议发现能够抑制该因子增加BC进展的能力的化合物。我们发现RUNX2因子通过增加葡萄糖代谢、抑制线粒体呼吸和减少上皮特异性基因表达或分化促进BC进展为更具侵袭性的转移形式。我们还使用实验室开发的新型药物筛选方法和活性测定来表征与抑制RUNX2因子和BC生长的维生素D相关的几种化合物。鉴于这些观察结果，在VA Merit更新申请中，我们提出了RUNX2因子可以改变BC代谢并抑制细胞分化同时促进肿瘤进展的假设。我们进一步提出，使用新型维生素D衍生物靶向抑制该因子将恢复正常的细胞代谢和分化，防止肿瘤进一步进展，并抑制BC生长。 因此，本提案的目标是对RUNX2介导的乳腺癌生长和分化之间的关系进行全面但集中的分析。RUNX2可能促进有利于糖酵解和抑制线粒体呼吸的代谢进程。几种特定的BC细胞模型和促进BC细胞分化的新型化合物将用于确定调节乳腺癌进展和转移的机制。目的是（1）确定BC细胞分化、代谢和进展之间RUNX2调节的关系，（2）确定维生素D3前激素如何通过其调节细胞代谢来调节RUNX2 DNA结合和BC分化，以及（3）确定维生素D3氧化变体调节RUNX2 DNA结合和BC分化的机制。退伍军人管理局医疗保健系统中的许多患者也患有肺癌，结直肠癌和头颈癌，这些癌症在吸烟的老年退伍军人中很常见。我们的研究可能为了解调节这些恶性肿瘤的分子途径提供见解。由于我们正在测试的假设也与RUNX2如何调节血管疾病有关，因此本研究中发现的治疗靶向策略可能对退伍军人群体中流行的其他病理具有适用性和临床意义， 会因年龄增长和吸烟而恶化，如心血管疾病。!

DESCRIPTION (provided by applicant): Breast cancer (BC) continues to be the most common cancer in women and is responsible for almost 40,000 deaths per year. According to the VA Center for Women Veterans, women are the fastest growing subgroup of U.S. veterans and this number is expected to grow in the next 10 years. Therefore, as the population ages, VA health care will be in high demand by women veterans. This is because some of the same risk factors that are associated with poor prognosis in the general population are also found in the VA population. The VA also treats a moderately high volume of male BC and, unlike the declining mortality for female BC, death rates from male BC have not decreased. Compared with the general population, a higher proportion of the male and female BC patients in the VA system are African-American, relative to the private sector, and this population exhibits higher mortality and morbidity rates. Therefore, identifying effective therapeutic targets to treat these diverse groups of veterans is highly relevant to the VA patient care mission. The previous VA Merit funded project addressed questions about how breast cancers acquire hormone independence and become metastatic or spread throughout the body. We suspected that this type of tumor progression was controlled by a BC protein (RUNX2) that regulates expression of genes that promote growth and metastasis. We also proposed to discover compounds that would inhibit the ability of this factor to increase BC progression. We found that the RUNX2 factor promotes BC progression to a more aggressive, metastatic form by increasing glucose metabolism, inhibiting mitochondrial respiration, and reducing epithelial- specific gene expression, or differentiation. We also used novel drug screening methods and activity assays developed in the laboratory to characterize several compounds related to vitamin D that inhibited the RUNX2 factor and BC growth. Given these observations, in this VA Merit renewal application we propose the hypothesis that the RUNX2 factor can alter BC metabolism and inhibit cell differentiation while promoting tumor progression. We further propose that targeted inhibition of this factor using novel vitamin D derivatives will restore normal cell metabolism and differentiation, prevent further tumor progression, and inhibit BC growth. The goal of this proposal, therefore, is to perform a comprehensive but focused analysis of the relationship between RUNX2-mediated breast cancer growth and differentiation. RUNX2 may promote a metabolic progression favoring glycolysis and suppressing mitochondrial respiration. Several specific BC cell models and novel compounds that promote BC cell differentiation will be used to define the mechanisms regulating breast cancer progression and metastasis. The goals are to (1) define the RUNX2-regulated relationship between BC cell differentiation, metabolism, and progression, (2) define how Vitamin D3 prohormone regulates RUNX2 DNA binding and BC differentiation through its regulation of cell metabolism, and (3) determine the mechanisms regulating RUNX2 DNA binding and BC differentiation by oxidized variants of Vitamin D3. Many patients within the Veterans Administration health care system also suffer from lung, colorectal, and head/neck cancers, which are prevalent in elderly veterans who are smokers. Our study may provide insight into understanding the molecular pathways regulating these malignancies. Because the hypotheses we are testing are also relevant to how RUNX2 regulates vascular disease, therapeutic targeting strategies discovered in this study may have applicability and clinical relevance for other pathologies prevalent in the veteran population that are exacerbated by aging and smoking, such as cardiovascular disease. !