Inhibition of leptin-signaling axis in breast cancer by BITC

BITC 对乳腺癌瘦素信号轴的抑制

• 批准号: 8635831
• 负责人: Dipali Sharma
• 金额: $ 21.14万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8635831
• 关键词: Abdomen; Adipocytes; Age; Binding; Biological Assay; Body mass index; Breast Cancer Cell; Breast Cancer Risk Factor; Breast Carcinogenesis; Breast Epithelial Cells; Cancer Patient; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Trials Design; Coculture Techniques; Data; Death Rate; Diet; Effectiveness; Epithelial; Exhibits; Gene Targeting; Goals; Growth; Knockout Mice; Knowledge; Lead; Leptin; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mesenchymal; MicroRNAs; Modeling; Molecular; Molecular Profiling; Molecular Target; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Obesity; Outcome; Overweight; Pathway interactions; Phosphorylation; Preventive Intervention; Regimen; Research; Role; Signal Transduction; Testing; United States National Center for Health Statistics; Wild Type Mouse; Woman; Work; base; benzyl isothiocyanate; bioactive food component; cancer prevention; cancer risk; combat; cruciferous vegetable; epithelial to mesenchymal transition; gain of function; high risk; in vivo; innovation; leptin receptor; malignant breast neoplasm; migration; mortality; neoplastic; novel; outcome forecast; overexpression; pandemic disease; paracrine; pre-clinical; prevent; public health relevance; response; tumor progression

PROJECT SUMMARY/ABSTRACT The condition of being overweight or obese has been implicated as a risk factor for breast cancer. According to the National Center for Health Statistics (NCHS), ~42.3% of women ages 50 and older in US are obese whose breast cancer risk is increased two- to four- fold. Furthermore, the current pandemic of obesity can potentially lead to a corresponding increase in breast cancer world-wide. There is a clear and compelling need to develop chemopreventive strategies to combat breast cancer in obese population. With an overall goal to develop effective chemopreventive strategies to target breast cancer in obese state, in this proposal, we will examine the molecular mechanism(s) whereby Benzyl isothiocyanate (BITC), a bioactive compound derived from cruciferous vegetables, prevents breast cancer growth in obese hyperleptinemic conditions. Research from our lab and others has shown that high leptin levels (hyperleptinemia) associated with obese state is a major driver of breast cancer progression and metastasis. Examining bioactive approaches to block leptin signaling, we recently discovered that BITC can effectively reduce leptin-induced proliferation and blocks leptin-induced migration potential of breast cancer cells. The project consists of two highly innovative aims. Aim 1 will test whether BITC blocks leptin-induced epithelial-mesenchymal transition, inhibits leptin-signaling network and examine the role of miR-34a in mediating BITC actions. Our studies will establish BITC as an effective leptin- antagonist and dissect the underlying molecular interactions between BITC and leptin signaling axes potentially revealing new crosstalk. Aim 2 will focus on examining whether BITC impedes paracrine actions of leptin and prevents breast carcinogenesis in hyperleptinemic obese state. Our preliminary findings show that the paracrine effect of leptin is important for adipocytes-breast cancer cells crosstalk leading to induction of EMT, invasion and migration potential of breast cancer cells. Results from this aim will decipher if BITC can block paracrine effects of leptin and prevent adipocytes-breast cancer cells crosstalk outcome. Our studies will advance the BITC chemoprevention field in a new direction showing the effectiveness of BITC in preventing breast cancer progression in obese conditions and establishing BITC as a novel leptin-antagonist. These studies will provide pre-clinical information to design clinical trials of BITC-based chemopreventive strategies for obese persons at high risk for developing breast cancer. It is important to note that obesity is attributed to ~90,000 cancer-related deaths/year in the USA therefore our findings will have far-reaching impact.

项目摘要/摘要 超重或肥胖的状况已被视为乳腺癌的危险因素。根据 美国国家卫生统计中心（NCHS），在美国，约42.3％的妇女是肥胖的 乳腺癌风险增加了两到四倍。此外，肥胖的当前大流行可能可能 导致全世界乳腺癌的相应增加。有明确而迫切的发展需要 在肥胖人群中打击乳腺癌的化学预防策略。总体目标是发展 有效的化学预防策略将靶向肥胖状态的乳腺癌靶向，在此提案中，我们将检查 分子机制，苯甲酸异硫氰酸苯甲酸酯（BITC），这是一种生物活性化合物 十字花科蔬菜，可防止肥胖的高肠病毒状况下的乳腺癌生长。我们的研究 实验室和其他人表明，与肥胖状态相关的高瘦素水平（高瘦素血症）是主要驱动因素 乳腺癌的进展和转移。检查生物活性方法以阻断瘦素信号传导，我们 最近发现BITC可以有效地减少瘦素诱导的增殖并阻止瘦素诱导的 乳腺癌细胞的迁移潜力。该项目由两个高度创新的目标组成。 AIM 1将测试 BITC是否阻止瘦素诱导的上皮 - 间质转变，抑制瘦素信号网络和 检查miR-34a在介导BITC作用中的作用。我们的研究将确定BITC作为有效的瘦素 - 拮抗剂并剖析BITC和瘦素信号轴之间的基本分子相互作用 有可能揭示新的串扰。 AIM 2将专注于检查BITC是否阻碍了旁分泌作用 瘦素并阻止乳腺癌肥胖状态下的乳腺癌发生。我们的初步发现表明 瘦素的旁分泌作用对于脂肪细胞 - 胸癌细胞串扰很重要，导致诱导 EMT，乳腺癌细胞的侵袭和迁移潜力。如果BITC可以，此目标的结果将破译 阻断瘦素的旁分泌作用并预防脂肪细胞 - 胸癌细胞串扰结局。我们的研究将 将BITC化学预防领域推进了一个新的方向，显示了BITC的有效性 乳腺癌在肥胖条件下的进展，并将BITC确立为新型瘦素抗抗激素。这些 研究将提供临床前信息，以设计基于BITC的化学预防策略的临床试验 对于患乳腺癌高风险的肥胖者。重要的是要注意肥胖归因于 在美国，〜90,000次与癌症相关的死亡人数，因此我们的发现将产生深远的影响。