瘦素参与降低ERα阳性乳腺癌对他莫西芬敏感性的机制研究

Leptin, a circulating peptide hormone,is involved in the carcinogenesis and development of breast cancer. Functional cross-talk between leptin and estrogen signaling has been registered.However, little has been known about the role of leptin in the treatment of estrogen receptor positive breast cancer. We have demonstrated that simultaneous treatment with leptin significantly attenuated the inhibition of tamoxifen on the proliferation of MCF-7 cell by stimulating the transcription of estrogen receptor alpha. On the contrary,we also showed that transfection of siRNA targeted to leptin receptor significantly inhibited the proliferation of MCF-7 cells and increased the apoptosis rates. We hypothesize the leptin may be involved in the resistance to tamoxifen in estrogen receptor positive breast cancer cells, and targeted therapy aimed to leptin signaling may synergistically improve the treatment effect of tamoxifen. We will explore the roles and mechanisms of leptin involved in the resistance to tamoxifen in MCF-7 cells from the molecular, cytologic, histological and animal aspects by using real-time PCR, western blot, gene transfection, RNA interference,etc. Our study results will give a new insight into the complex mechanisms of resistance to tamoxifen. The outcomes will also provide a new way to improve the therapeutiv effect of estrogen receptor positive breast cancer.

瘦素是一种多肽类激素，参与了乳腺癌的发展过程。瘦素信号通路与雌激素信号通路之间存在功能性的交叉。但是关于瘦素在雌激素受体（ER）阳性乳腺癌治疗上的意义还知之甚少。我们的研究发现肿瘤组织中瘦素表达的患者应用他莫西芬（TAM）的疗效较差，血清瘦素水平在TAM无效的患者中较高。瘦素通过刺激ERα的转录导致MCF-7细胞中ERα的表达增高，从而削弱TAM的雌激素阻断作用。干扰瘦素受体表达可抑制MCF-7细胞的增殖并诱导凋亡。我们假设，瘦素可能降低了TAM的敏感性，针对瘦素通路的治疗可能提高TAM的疗效。我们拟应用乳腺癌细胞株，采用定量PCR、Western blot、基因转染、RNA干扰等手段，从分子、细胞以及动物水平探讨瘦素降低TAM敏感性的作用及其相关机制，明确针对瘦素受体的治疗联合TAM是否能协同增效。本研究将从瘦素信号通路的新视点揭示TAM耐药的机制，为提高乳腺癌的疗效提供新的思路。

瘦素（LEP）是一种强效的脂肪因子，与乳腺癌的发生发展有着密切关联，并能削弱他莫昔芬抑制乳腺癌细胞增殖的作用，从而参与他莫昔芬的耐药过程。本项研究旨在探讨瘦素在他莫昔芬治疗耐药中的分子机制并评估在人乳腺癌细胞株MCF-7和他莫昔芬耐药的MCF-7细胞株（TAM-R）中敲低瘦素受体（OBRb）后对于他莫昔芬治疗敏感性的影响。我们检测了OBRb在乳腺癌的表达，回顾性的分析了LEP及OBRb与乳腺癌预后的关系，发现在乳腺癌中OBRb高表达，且与不良预后相关。LEP可促进雌激素受体阳性乳腺癌细胞的ERα的转录增加而促进其表达，进而促进了乳腺癌的增殖。机制研究发现LEP诱导的细胞增殖效应增强与细胞外信号调节激酶 （ERK）1/2及信号转导和转录激活因子（STAT）3信号转导通路的激活以及 CCND1的上调有关。瘦素通过诱导ERα与CCND1 基因启动子的结合从而增强CCND1 基因的转录活性。鉴于雌激素受体阳性乳腺癌患者内分泌治疗的重要性以及耐药的普遍性，我们进一步考察了LEP与乳腺癌抗雌激素受体治疗的耐药关系。发现瘦素受体的敲低能提高TAM的敏感性，显著增强了TAM耐药细胞（TAM-R）对他莫昔芬的敏感性，机制研究证实敲低ObRb能够增强TAM对TAM-R细胞增殖通路的抑制作用。本项目研究表明，内分泌治疗可上调乳腺癌细胞中瘦素和瘦素受体的表达，从而通过激活 ERK1/2 和 STAT3 信号转导通路以及上调CCND1基因的表达而削弱他莫昔芬对乳腺癌细胞增殖的抑制作用。瘦素受体的敲低可能对于逆转ER阳性乳腺癌患者的他莫昔芬耐药是一个新的选择。