MYSM1在乳腺癌内分泌治疗耐药中的调控作用及机制研究

Breast cancer is the most common tumor in women. Estrogen receptor (ER) in 70% of patients is positive. Tamoxifen (TAM) is used as the principle endocrine drug for the treatment of ER+ breast cancer. However, TAM-resistance after treatment becomes a problem to clinical oncologist, and the mechanism of the TAM-resistance remains unclear. Our preliminary experiments found that the expression levels of nuclear receptor co-regulators MYSM1 were elevated in TAM-resistant patients. We also found that the co-activated factor PCAF was increased and the co-suppressed factor NCoR was reduced. These results suggest that MYSM1 plays a key role in regulation of TAM-resistance. This project will explore the cause and mechanism conduced the abnormal expression of co-regulators mentioned above. In order to define the relationship between MYSM1 and TAM-resistance, we will detect the protein expression levels of MYSM1 in TAM-resistant breast cancer tissues and cells, and the cells with altered MYSM1 expression levels will be used in vitro and in vivo. In additionally, we will clarify whether MYSM1 can up-regulate or recruit PCAF protein or enhance the acetylates activity of PCAF, which result in the transcription activation of ER-dependent genes and TAM-resistance in breast cancer, by means of chromatin immunoprecipitation assay (ChIP), acetylation, luciferase reporter system. This study will propose a new mechanism of TAM-resistance and provide a novel insight into the treatment to TAM-resistant breast cancer.

乳腺癌是最常见女性恶性肿瘤，约70%患者雌激素受体（ER）为阳性。三苯氧胺(TAM)是ER阳性乳腺癌内分泌治疗主要药物，易产生抗药性，这是临床面临的难题；具体耐药机制尚未清楚。本课题预实验发现TAM耐药时核受体调节蛋白MYSM1表达明显升高，ER共激活因子PCAF增加以及共抑制因子NCoR减少，提示MYSM1在TAM耐药中起重要调节作用。本项目拟检测TAM耐药乳腺癌组织和细胞中MYSM1表达情况，并通过改变MYSM1表达量在体内和体外水平分析其与TAM耐药之间的关系；采用染色体免疫共沉淀、乙酰化实验、荧光素报告检测系统等研究手段，阐明MYSM1通过招募或上调PCAF的表达/加强PCAF的组蛋白乙酰化功能，增强ER靶基因的转录水平，揭示MYSM1高表达后促进乳腺癌TAM耐药的机制。本研究将为乳腺癌TAM耐药研究提供新的线索，为改善临床乳腺癌内分泌治疗奠定基础。

乳腺癌是最常见的女性恶性肿瘤，是妇女死亡的主要原因之一。三阴性乳腺癌(TNBC)由于缺乏治疗受体，是乳腺癌中恶性程度最高、预后最差的分型之一，临床上缺乏靶向治疗手段，常规化疗易产生耐药。前期研究发现细胞耐药时，核受体调节蛋白MYSM1表达明显升高，共激活因子增加、共抑制因子减少，提示MYSM1在耐药中起重要调节作用。本研究证实了MYSM1作为一种H2A去泛素酶(DUB)在TNBC中的功能。MYSM1在乳腺癌中表达显著降低，尤其是在TNBC中，提示潜在的抑癌作用。在TNBC细胞系中过表达和抑制MYSM1的表达会导致细胞增殖发生显著的生物学变化。此外，MYSM1过表达增加了顺铂诱导的细胞凋亡，这与RSK3的失活以及Bcl-2细胞死亡拮抗剂受体(BAD)磷酸化水平(Ser 112)的降低有关。本研究揭示MYSM1可作为TNBC中调节细胞凋亡和抑制顺铂耐药的潜在靶点；为乳腺癌耐药研究提供新的线索，为改善临床乳腺癌治疗奠定基础。