KDM2A/ASH2L在ER阳性乳腺癌他莫昔芬耐药中的作用及机制研究

Tamoxifen (TAM) is the most commonly used drug as an endocrine therapy for estrogen receptor (ER)-positive breast cancer patients. However, TAM resistant is one of the main reason for treatment failure to breast cancer. Our recent work has investigated that histone lysine demethylase KDM2A plays a critical role in progression of breast cancer, particularly in aggressive ER-positive subtype. Knockdown KDM2A could inhibit proliferation and malignant phenotype in ER-positive breast cancer cell with TAM resistant. Interestingly, our unpublished data revealed that KDM2A is associated with ASH2L, the component of the MLL/ASH2 histone methyltransferase complex, which affects ER transcriptional activity. Both KDM2A and ASH2L are commonly amplified and highly expressed in aggressive subsets of TAM-resistant breast cancers. In this proposal, we hypothesize that KDM2A and ASH2L are key contributing factors to TAM resistance of breast cancer through epigenetic regulation of ER-dependent transcriptional program. Accordingly, we will use clinical breast cancer specimens and cell lines, immunohistochemical and molecular biological approaches, as well as animal models to investigate the clinical significance and molecular mechanism of KDM2A/ASH2L in contributing TAM-resistance of breast cancers. Thus, this proposal will provide new strategy and molecular targets to improve the prognosis for breast cancer, representing research that is directly relevant to the treatment of breast cancer patients.

它莫西芬（TAM）是雌激素（ER）阳性乳腺癌内分泌治疗应用最广泛的药物，但TAM耐药是乳腺癌临床治疗失败的最主要原因之一。我们最近研究显示KDM2A在ER阳性乳腺癌中具有非常关键的作用，沉默KDM2A可抑制TAM耐受的ER阳性乳腺癌细胞的增殖和恶性表型。ASH2L是调节ER转录活性的MLL/ASH2L组蛋白甲基转移酶复合体的一部分。我们未发表的数据表明KDM2A与ASH2L可结合在一起。KDM2A和ASH2L在TAM耐药的乳腺癌中都具有较高的基因扩增频率和mRNA过表达。本课题拟采用临床乳腺癌标本、细胞系、免疫组化和动物实验等研究KDM2A/ASH2L在乳腺癌TAM耐药中临床意义和分子机制，从而阐明KDM2A和ASH2L是乳腺癌TAM耐药的关键影响因素并通过表观遗传调控ER转录。该项目是前期研究的进一步深入和延续，为改善ER阳性乳腺癌患者预后提供新的思路，有望开辟新的治疗靶点。

它莫西芬(TAM)是雌激素(ER)阳性乳腺癌内分泌治疗应用最广泛的药物，但TAM耐药是乳腺癌临床治疗失败的最主要原因之一。我们最近研究显示KDM2A在ER阳性乳腺癌中具有非常关键的作用，沉默KDM2A可抑制TAM耐受的ER阳性乳腺癌细胞的增殖和恶性表型。 ASH2L是调节ER转录活性的MLL/ASH2L组蛋白甲基转移酶复合体的一部分。我们的实验数据表明KDM2A与ASH2L可结合在一起。KDM2A和ASH2L在TAM耐药的乳腺癌中都具有较高的基因扩增频率和mRNA过表达。本课题采用临床乳腺癌标本分析、细胞系、免疫组化和动物实验等研究KDM2A/ASH2L在乳腺癌TAM耐药中临床意义和分子机制。目前结果显示沉默KDM2A后的乳腺癌细胞系经TAM处理后细胞增殖有抑制，但抑制不明显，我们认为这与KDM2A短亚型的致癌作用有关，而我们WB显示KDM2A的长亚型比短亚型沉默效果好，也因此TAM处理后的抑制效果不明显。高通量测序可以为我们提供沉默KDM2A或ASH2L后细胞系经TAM处理后可能的差异基因，因此为研究乳腺癌中TAM耐药提供新的思路。