GGH在基底型乳腺癌的作用与机制研究

乳腺癌是一种高度异质性的疾病，其中基底型乳腺癌恶性程度最高，预后最差。目前，基底型乳腺癌的代谢调控机制仍有待于深入研究。GGH是一种溶酶体酶，与叶酸代谢密切相关。在溶酶体中GGH可以水解叶酰多聚谷氨酸生成叶酰单谷氨酸。我们前期研究发现：GGH在基底型乳腺癌中明显高表达；GGH过表达可以明显降低乳腺癌细胞内的叶酸水平，增强细胞克隆成球能力，促进HIF-1ɑ的表达，抑制E-cadherin表达并且使乳腺癌细胞形态发生EMT样改变。GGH敲降明显抑制乳腺癌的侵袭和迁移。此外，我们发现Sox10可以明显促进GGH的表达。基于上述基础，本项目计划揭示GGH参与基底型乳腺癌的发生、发展的分子机制，解析Sox10调控GGH表达分子机制，评估Sox10/GGH与基底型乳腺癌的临床病理关系，探讨GGH临床应用的意义与价值，为临床基底型乳腺癌的治疗提供潜在的分子标记物。

Breast cancer is a heterogeneous disease ，and basal-like breast cancer is the most aggressive breast cancer and has the worst poor prognosis. The mechanism metabolic regulation of breast cancer still needs to be further studied at present.GGH is a lysosomal enzyme that is closely related to folate metabolism. In lysosomes, GGH can hydrolyze polyglutamyl folates into monoglutamyl folates. Our previous research found that: GGH is significantly overexpressed in basal-like breast cancer; GGH overexpression significantly reduced the level of folic acid in breast cancer cells, enhanced the mammaspheres, promoted the expression of HIF-1ɑ, inhibited the expression of E-cadherin, and induced EMT-like changes in morphology. GGH knockdown significantly inhibits the invasion and migration of breast cancer cell. In addition, we found that Sox10 can significantly promote GGH expression. Based on these basis, the project plans to reveal the molecular mechanism of GGH involved in the occurrence and development of basal-like breast cancer, analyzes the molecular mechanism of Sox10 regulating GGH expression, evaluates the clinicopathological relationship between Sox10 / GGH and basal-like breast cancer, and explores the significance of clinical application of GGH and value, also provides potential molecular marker for the treatment of basal-like breast cancer.