申请者研究发现 miR-34a能抑制乳腺癌的生长、侵袭与转移，诱导乳腺癌细胞凋亡。自主发明的hTERT-VISA-miR-34a（TV-miR-34a，中国发明专利），可高效、持续表达miR-34a，具有抑制MMTV-Wnt-1转基因小鼠自发成瘤及肺转移的能力，并证实TV-miR-34a可通过靶向抑制CD44与Wnt-1进而抑制Wnt-β-catenin 信号通路，抑制乳腺癌干细胞的生长侵袭，诱导乳腺癌干细胞凋亡。尽管miR-34a在乳腺癌功能和作用机制上取得了一些初步结果，但仍然缺乏强有力的体内实验依据。因此，本项目通过构建miR-34a条件基因剔除小鼠模型，进一步明确miR-34a抑制乳腺癌及乳腺癌干细胞生长与侵袭的分子机制，从而全面揭示miR-34a在乳腺癌发生发展中的作用。为TV-miR-34a作为一种新的乳腺癌靶向药物提供实验依据。

The applicant have previouslydemenstrated that overexpression of miR-34a inhibited the proliferation,invasion and metastasis, induced cell apoptosis in breast cancer. Self-created TV-miR-34a (China invention patent) could express miR-34a efficiently and persistently, and inhibit spontaneous tumor formation and lung metastasis of MMTV-Wnt-1 transgenic mice. We also identified that TV-miR-34a could inhibit proliferation, invasion and induce apoptosisof breast cancer stem cells by targeting CD44 and Wnt-1 signaling. Although having some preliminary experimental information on the role of miR-34a in tumorigenesis, it's still lack the strong evidence in vivo. This project aims to construct the miR-34a knockout mouse models and use these mouse models to investigate the effects of miR-34a deletion on mouse spontaneous tumor formation, then further investigate the molecular mechanisms that miR-34a inhibit proliferation and invasion of breast cancer and breast cancer stem cells, thus reveal the mechanisms of miR-34a as a tumor suppressor. This project will provide experimental evidences for developing TV-miR-34a as a novel therapeutic strategie in breast cancer treatment.