衔接蛋白Ndfip1与E3泛素化连接酶Nedd4-1调节PTEN稳定性，是乳腺癌产生化疗耐药的机制之一。新近研究表明非编码RNA和焦亡在乳腺癌进展和化疗耐药中发挥重要作用。我们前期实验证实，乳腺癌组织Ndfip1/Nedd4-1高表达而PTEN失活，两者能诱导MCF-7细胞化疗耐药；耐药细胞MCF-7/ADM高表达hsa_miR_0014246而miR-421下调。由此我们提出：hsa_miR_0014246靶向miR-421调控Ndfip1/Nedd4-1/PTEN通路导致乳腺癌细胞焦亡抑制和耐药产生。为此，本课题拟以细胞模型转染hsa_miR_0014246和miR-421表达质粒和iRNA，研究其对Ndfip1/Nedd4-1泛素化系统的影响，探讨其通过焦亡影响乳腺癌细胞生长和多药耐药作用，深入研究分子机制，进一步在动物模型和临床验证，有助于为乳腺癌治疗和耐药逆转提供新的靶点。

Cohesion protein Ndfip1 and E3 ubiquitinated ligase Nedd4-1 regulate PTEN stability, which is one of the mechanisms of chemotherapeutic resistance in breast cancer. Recent studies have shown that non-coding RNA and pyroptosis play an important role in the progression and chemotherapy resistance of breast cancer. Our previous experiments confirmed that Ndfip1/Nedd4-1 was overexpressed and PTEN was inactivated in breast cancer tissues, both of which could induce chemotherapy resistance in MCF-7 cells, while the drug-resistant cells MCF-7/ADM overexpressed has_mir_0014246 and down-regulated mi-421. Therefore, we propose that hsa_circ_0014246 targeting RNA-421 regulates Ndfip1/Nedd4-1/PTEN pathway leading to pyroptosis inhibition and drug resistance in breast cancer cells. To this end, we intend to transfect hsa_circ_0014246 and Mi-421 expression plasmids and iRNA into cell models to study their effects on Ndfip1/Nedd4-1 ubiquitination system, to explore their effects on breast cancer cell growth and multidrug resistance through pyroptosis， to further study the molecular mechanism, and to validate in animal models and clinical trials, so as to provide new targets for breast cancer treatment and drug resistance reversal.