长期雌激素(E2)刺激是乳腺癌的一个主要诱发因素,机制尚未彻底阐明。研究表明,E2受体(ERα)辅助因子在ERα通路中发挥重要作用，其抑制剂是乳腺癌治疗新靶点。我们前期研究就发现这样一个因子，即肽基精氨酸脱亚胺酶II(PADI2)，它通过催化组蛋白H3 N-末端第26位精氨酸的鸟氨酸化(H3Cit26)促进E2应答元件区染色质开放，影响靶基因转录；我们预试验也证实PADI抑制剂能抑制乳腺癌细胞增殖,提示PADI2可能成为乳腺癌防治新靶点。为验证此假说,我们将进一步阐明PADI2与ERα相互作用机制,揭示PADI2在ERα阳性乳腺癌细胞中基因转录调控分子机理；在此基础上，研究PADI2及H3Cit26与乳腺癌发生发展关系,观察PADI抑制剂对ERα阳性乳腺癌细胞及对内分泌治疗耐受乳腺癌细胞的影响。本课题将为乳腺癌,尤其对内分泌治疗耐受乳腺癌的防治提供新的思路和药物靶点，弥补内分泌治疗的不足。

Breast cancer is the most common malignant tumor in women, and lifetime exposure to estrogen constitutes a major risk factor for breast cancer initiation and development, though the detailed molecular mechanisms are far more from complete. Accumulating evidence suggest that some cofactors for estrogen receptor α (ERα) can modulate target gene activities in estrogen-ERα signaling pathway by posttranslationally modifying histone tails at gene promoters, therefore, drugs targeting such epigenetic modifiers which are often overexpressed in hormonal breast cancers can be potentially used for therapeutic targeting. In our previous studies, for the first time, we identified that peptidylarginine deiminase (PADI) 2 catalyzes citrullination of histone H3 arginine 26 (H3R26) at decondensed chromatin loci surrounding the estrogen-response elements of target promoters and promotes target gene transcription upon estrogen stimulation; Our preliminary data also showed that PADI enzyme inhibitor, Cl-amidine, inhibits MCF-7 cell proliferation, suggesting that PADI2, which plays an important role in ERα signaling, represents a promising target for hormonal breast cancer treatment. To prove this hypothesis, we propose to further explore the molecular mechanisms underlying the interaction between PADI2 and ERα, and the role PADI2 plays in regulation of estrogen response gene transcription in ERα-positive breast cancer cells. Then, the expression of PADI2 and PADI2-catalyzed H3Cit26 will be assessed in breast caner progression tissue microarray in order to indicate the relevance to the clinical progression of breast cancer malignant behavior. Finally, Cl-amidine will be used to treat ERα-positive breast cancer cells, especially the cells that are resistant to endocrine therapy. Our proposals may provide both novel epigenetic target and treatment regimen(s) in breast cancer to overcome endocrine drug resistance.