SULT1E1在乳腺上皮细胞到乳腺癌细胞转化过程中的调控作用机制

The development of breast cancer is closely related to high levels of estrogen. Estrogen sulfortransferase SULT1E1 was the key enzyme of estrogen sulfation, could transformed estrogen to estrogen sulfates, which influences its biological activity. It has reported that loss of SULT1E1 expression maybe played crucial roles in the malignant transformation of normal mammary epithelial to breast cancer. Our previously study suggested that overexpression of SULT1E1 in MCF-7 cells inhibited estrogen-induced proliferation and promoted apoptosis; Interference of SULT1E1 regulated inflammation response and lipid metabolism by up-regulating PPARγ in HUVECs. These suggested that there was a link between SULT1E1 and PPARγ. Based on the above basis for our work, we further study the mechanism of SULT1E1 regulate PPAR on the malignant transformation of normal mammary epithelial to breast cancer using gene transfection and ChIP in vitro and in vivo; meanwhile, we analyze the correlation of SULT1E1 with tumorgenesis and prognosis based on the clinical pathological data. Our present study will provide new insight into SULT1E1 protective function on breast cancer development.

高雌激素水平和乳腺癌的发生密切相关。硫酸基转移酶SULT1E1是雌激素硫酸化反应的关键酶，可将雌激素转化为硫酸化雌激素影响其生物活性。有文献报道，SULT1E1的表达缺失在正常乳腺上皮转化为乳腺癌的过程中发挥重要作用。我们的前期研究发现，在MCF-7中过表达SULT1E1，可抑制细胞增殖促进细胞凋亡；而在血管内皮细胞HUVEC中，干扰SULT1E1可影响PPARγ的表达进而影响脂质代谢分子和炎症因子的释放，提示SULT1E1和PPARγ之间有一定的联系。基于前期的工作基础，本研究拟主要应用基因转染、染色质免疫共沉淀等技术，通过体、内外实验探讨SULT1E1是否通过调控PPARγ影响正常乳腺上皮到乳腺癌细胞的恶性转化；同时利用临床病理资料分析SULT1E1和PPARγ的表达与肿瘤发生及预后的相关性，为阐明SULT1E1对乳腺癌发生的保护作用机制提供理论依据和实验基础。

SULT1E1作为硫酸转移酶家族的成员之一，在雌激素相关性肿瘤如乳腺癌以及子宫内膜癌的发生发展方面关系密切。我们前期研究发现SULT1E1在正常乳腺上皮细胞中表达丰度较高，而在乳腺癌细胞中表达较低，但具体机制尚不明确。在本项目中我们通过在乳腺癌细胞中过表达SULT1E1，通过CCK-8实验、细胞周期检测分析、侵袭实验和流式细胞仪分析等手段来研究SULT1E1对乳腺癌细胞增殖和侵袭的影响及其分子机制。结果表明，乳腺癌细胞中过表达SULT1E1可诱导细胞凋亡、阻滞细胞周期进而抑制细胞的增殖；细胞的侵袭能力也显著下降。深入研究发现，SULT1E1通过激活PPARgamma来下调C-myc, Cyclin D1, MMP-2 and MMP-9 的表达进而影响细胞的凋亡和侵袭。体内裸鼠成瘤实验亦证实过表达SULT1E1可显著抑制移植瘤的生长。本研究阐明了在乳腺癌细胞中过表达SULT1E1可通过上调PPARgamma的水平来发挥它的抗肿瘤效应，为乳腺癌患者的靶向药物治疗提供了新的分子靶标。