TRIM24调控PRA表达影响内分泌治疗敏感性的机制研究

内分泌治疗敏感性决定着雌激素受体（ER）阳性乳腺癌的疗效，提高内分泌治疗效果是乳腺癌治疗领域迫切需要解决的重大课题。最新研究显示孕激素受体（PR）可以通过调控ER的活性影响内分泌治疗反应性。我们前期发现：PR两个亚型中的PRA表达相对高的患者对他莫昔芬治疗不敏感，体外研究发现PRA启动子区组蛋白乙酰化修饰水平较高，而PRA表达又与组蛋白乙酰化修饰调控基因TRIM24表达呈正相关，并且TRIM24过表达可以增加PRA占比，降低肿瘤对TAM的敏感性。本项目拟从细胞、动物、临床标本水平，利用细胞生物学、分子生物学等多种研究方法，重点研究TRIM24调控PRA转录的分子机制，进而揭示PRA通过调控ER功能影响内分泌治疗敏感性的机制。本研究有助于揭示PR影响ER对内分泌治疗的效果，为临床提高乳腺癌内分泌治疗效果提供理论依据和药物作用靶点。

The sensitivity of Endocrine therapy determines the therapeutic efficacy of estrogen receptor (ER) positive breast cancer, and improvement of efficacy is the major issue urgently to be solved in the field of breast cancer treatment. Progesterone receptor (PR) can affect the response of endocrine therapy by regulating the activity of ER, but its exact mechanism of action is unclear. Our previous study found that patients with high expression of PRA (PR subtype) were not sensitive to tamoxifen therapy. In vitro studies found that higher level of acetylation modification exists on PRA promoter region, PRA expression was positively correlated with TRIM24 expression, and TRIM24 overexpression increased proportion of PRA, to decrease the sensitivity of TAM. This study aims to study the molecular mechanism on regulation of PRA transcription by TRIM24, from levels of cell, animal, clinical specimen, using cell biology, molecular biology and other research methods, and then reveals the regulatory mechanism that PRA determines the sensitivity of endocrine therapy by affecting the function of ER. This study was helpful to reveal the effect of PR on endocrine therapy, and to provide theoretical basis and drug target for clinical improvement of endocrine therapy in breast cancer.