miR-29在乳腺癌内分泌治疗耐药与继发转移中的表观遗传机制

Tamoxifen as first-line drug for breast cancer endocrine treatment, due to breast cancer becoming resistance totamoxifen, and tamoxifen can induce endometrial cancer and other side effects of tamoxifen, recently developed a new breast cancer endocrine therapy drug, fulvestrant, like tamoxifen, breast cancer will ultimately become fulvestrant resistance. Our previous studies found that microRNA miR-29 in Fulvestrant resistant breast cancer cell lines significantly increased, and confirmed that miR-29 involved in the resistance to fulvestrant and secondary metastasis of breast cancer, but the mechanism of action is unclear. This project intends to use the drug-resistant cell lines and animal tumor models, DNA methylation chip, the CHIP-seq to detect DNA methylation, histone modifications and other epigenetic changes in drug-resistant cell lines, while studies of epigenetic changes in drug resistant breast cancer cells expressing or silencing miR-29, from epigenetic level investigate the mechanism of action of miR-29, and to explore the role of miR-29 in breast cancer stem cells epigenetic regulation, at the same time from epigenetic investigate the mechanism of how miR-29 was increased in the drug resistant cells, and finally reversal of breast cancer fulvestrant resistance and secondary metastasis through miR-29 inhibitor and epigenetic regulator.

三苯氧胺作为乳腺癌内分泌治疗一线药物，由于乳腺癌对三苯氧胺的耐药性以及三苯氧胺能够诱发子宫内膜癌等副作用，最近开发出了新的乳腺癌内分泌治疗药物氟维司群，和三苯氧胺一样，乳腺癌也最终会对氟维司群产生耐药性。我们的前期研究发现微RNA miR-29在氟维司群耐药乳腺癌细胞株中显著升高，并证实miR-29参与了乳腺癌对氟维司群的耐药及继发转移，但其作用机制还不清楚。本课题拟采用耐药细胞系及动物肿瘤模型，DNA甲基化芯片，CHIP-seq, 检测耐药细胞株的DNA甲基化分析，组蛋白修饰等表观遗传的变化，同时研究miR-29在乳腺癌耐药细胞表达或沉默后的细胞表观遗传的变化，从表观遗传方面探讨miR-29的作用机制，并探讨miR-29对乳腺癌干细胞表观遗传的调控作用，同时从表观遗传探明miR-29在耐药细胞中升高的机制，最后通过miR-29抑制剂和表观遗传调节剂逆转乳腺癌氟维司群耐药性及继发转移。

本项目主要从表观遗传方面探讨miR-29对乳腺癌内分泌治疗耐药和继发转移的分子机制。在四年的执行期中，我们通过高通量的二代测序技术及基因芯片分析发现了许多参与耐药和转移的小RNA，长链非编码RNA(LncRNA)及基因的甲基化，深入阐述了这些表观遗传的变化在乳腺癌内分泌耐药和转移中的分子机制。通过分子生物学和细胞生物学的方法详细的研究了miR-29对乳腺癌细胞表观遗传方面的影响，并探讨了miR-29对乳腺癌内分泌耐药及继发转移的分子机制。