Inhibition of leptin-signaling axis in breast cancer by BITC

项目总结/摘要 超重或肥胖的状况被认为是乳腺癌的一个危险因素。根据 根据美国国家卫生统计中心（NCHS）的数据，美国约42.3%的50岁及以上女性肥胖， 患乳癌的风险会增加二至四倍。此外，目前肥胖症的流行可能会 导致世界范围内乳腺癌发病率相应增加。有一个明确和迫切的需要， 化学预防策略来对抗肥胖人群中的乳腺癌。以发展为总目标 针对肥胖状态下乳腺癌的有效化学预防策略，在本提案中，我们将研究 异硫氰酸苄酯（BITC）是一种生物活性化合物， 十字花科蔬菜，防止乳腺癌的生长在肥胖高瘦素血症的条件。我们的研究 实验室和其他人已经表明，与肥胖状态相关的高瘦素水平（高瘦素血症）是肥胖的主要驱动因素， 乳腺癌的进展和转移。研究生物活性的方法来阻断瘦素信号，我们 最近发现，BITC可以有效地减少瘦素诱导的增殖，并阻断瘦素诱导的增殖。 乳腺癌细胞的迁移潜力。该项目包括两个高度创新的目标。目标1将测试 BITC是否阻断瘦素诱导的上皮-间质转化，抑制瘦素信号网络， 研究miR-34 a在介导BITC作用中的作用。我们的研究将建立BITC作为一种有效的瘦素- 拮抗剂和解剖BITC和瘦素信号轴之间的潜在分子相互作用 潜在地揭示新的串扰。目标2将侧重于研究BITC是否会阻碍 在高瘦素血症肥胖状态下，瘦素和预防乳腺癌发生。我们的初步调查结果显示， 瘦素的旁分泌作用对于脂肪细胞-乳腺癌细胞的串扰导致诱导 乳腺癌细胞的EMT、侵袭和迁移潜力。从这个目标的结果将破译，如果BITC可以 阻断瘦素的旁分泌作用，防止脂肪细胞-乳腺癌细胞的串扰结局。我们的研究将 将BITC化学预防领域推向一个新的方向，显示BITC在预防 肥胖条件下乳腺癌的进展，并建立BITC作为一种新的瘦素拮抗剂。这些 研究将为设计基于BITC的化学预防策略的临床试验提供临床前信息 为患乳腺癌风险高的肥胖人群提供治疗。值得注意的是，肥胖是由于 美国每年约有90，000例癌症相关死亡，因此我们的研究结果将产生深远的影响。

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.