Lats (Large tumor suppressor gene)2与乳腺癌相关，但Lats2介导的经典Hippo通路并不足以充分阐明其调控乳腺癌发生发展的机制。申请人预实验发现，Lats2结合并磷酸化Hh（Hedgehog）通路成员Sufu（Suppressor of fused)，Sufu磷酸化突变体上调Gli1转录活性。据此，申请人提出假说：Lats2磷酸化Sufu调控Hh通路抑制乳腺癌细胞增殖。本研究拟阐明Lats2磷酸化Sufu调控Hh通路的的分子机制；利用敲低或过表达方法并结合细胞和裸鼠乳腺癌模型研究Sufu野生型及磷酸化突变体在乳腺癌发生发展中的作用和细胞分子机理；利用乳腺癌临床标本，结合临床资料及TCGA等数据库，分析Lats2、Sufu等相关蛋白的表达和相关性，评价Lats2调控Hh通路的临床意义。该研究结果可能为乳腺癌的诊疗提供新思路和药物靶点。

Lats2 (Large tumor suppressor gene2) is associated with breast cancer, however, the the function of Lats2 in breast cancer tumorigenesis and development cannot be fully explained by Lats2-mediated canonical Hippo/Lats2 pathway. Our preliminary data showed that Lats2 binds to and phosphorylates suppressor of fused (Sufu), a key member of the Hedgehog (Hh) pathway. Furthermore, Sufu mutants that can not be phosphorylated by Lats2 upregulats the transcription activities of Gli1. Based on these observations, we hypothesize that Lats2 phosphorylates Sufu regulating the Hedgehog (Hh) pathway to inhibit breast cancer proliferation. To test this, we will dissect the molecular mechanisms by which Lats2 phosphorylates Sufu modulating the Hedgehog (Hh) pathway. Furthermore, by knock down or overexpressing Sufu and its phospho-ablatant mutants in breast cancer cells and nude mice tumor models, we will investigate the function of Sufu phosphorylation by Lats2 in breast cancer oncogenesis and development. Lastly, the expression of Lats2, Sufu and the Hippo/YAP pathway proteins will be examined in the breast cancer tissue samples and be analyzed in the Cancer Genome Atlas (TCGA) database and the correlation of Sufu phosphorylation and breast cancer grade will be analyzed. Together, we aim to elucidate the function and molecular mechanism of Lats2-mediated Sufu phosphorylation in tumorigenesis with the implication of a new target in the diagnosis and treatment of breast cancer.