一个新乳腺癌早发相关基因PTCH2影响乳腺癌发生的分子机制研究

Early-onset breast cancer has unique clinicopathological characteristics and worse prognosis, restricting the improvement of the diagnosis and treatment level of breast cancer in China, but fewer studies and limited knowledge regarding this cohort of patients. PTCH2, an inhibitor of Hedgehog pathway, was characterized as susceptibility gene of early-onset breast cancer in the preliminary work. PTCH2 is associated with tumorgenesis and progression, but its mechanism in breast cancer remains unclear. PTCH2 knockout increased cell proliferation and clone ability and led to downregulation of pten. Therefore, we concluded that PTCH2 promotes the occurrence of breast cancer by regulating Hedgehog and PI3K/Akt pathway. Our research will carry out the study on the driving mechanism of PTCH2 gene in the process of breast cancer, including the analysis of PTCH2 molecular function at cellular, animal and human histology level. The study above will make an in-depth exploration of the function and molecular mechanism of PTCH2, elucidating the mechanism of breast cancer earlier in China than Western countries and providing accurate screening for high-risk groups of early-onset breast cancer.

年轻乳腺癌临床病理特征侵袭性高、预后差，制约了中国乳腺癌整体诊疗水平的提高，但国内外相关研究甚少。前期工作基础筛选出中国早发性乳腺癌易感基因PTCH2，PTCH2作为Hedgehog信号通路的负调控因子，与肿瘤的发生发展相关，但在乳腺癌中的作用机制尚不明确。预实验证实PTCH2基因敲除促进细胞增殖、增强克隆形成能力，同时引起pten表达下调。因此我们提出假设：PTCH2通过交叉调控Hegdehog和PI3K/Akt信号通路促进乳腺癌发生。本课题拟针对PTCH2基因在乳腺癌发生过程中的驱动作用，从细胞、动物、人体组织水平研究PTCH2影响乳腺癌发生的分子机制，一方面有助于阐明中国乳腺癌早发于欧美国家的生物学机制，另一方面也有利于精准定位乳腺癌高危人群，为制定中国针对性防控和筛查策略提供科学指导。

年轻乳腺癌临床病理特征侵袭性高、预后差，制约了中国乳腺癌整体诊疗水平的提高，但国内外相关研究甚少。前期工作基础筛选出中国早发性乳腺癌易感基因PTCH2，PTCH2作为Hedgehog信号通路的负调控因子，与肿瘤的发病进展相关，但在乳腺癌中的作用机制尚不明确。本课题研究结果显示，PTCH2基因通过胚系突变或甲基化修饰促进乳腺癌的早发。PTCH2基因敲除会促进细胞增殖、克隆形成能力增强，在小鼠模型也验证了PTCH2敲除会导致乳腺导管发育异常，而且小鼠成瘤时间缩短。最后分子机制上进行研究，发现PTCH2通过调控PI3K和Hedgehog通路调控乳腺癌的早发。本课题针对PTCH2基因在乳腺癌发生过程中的驱动作用，从细胞、动物、人体组织水平研究PTCH2影响乳腺癌发生的分子机制，一方面阐明了中国乳腺癌早发于欧美国家的生物学机制，另一方面也有利于精准定位乳腺癌高危人群，为制定中国针对性防控和筛查策略提供科学指导。