生长抑制因子ING4逆转乳腺癌抗HER2耐药的作用及其机制

抗HER2靶向药物的原发和继发耐药是目前HER2+乳腺癌治疗的主要障碍。生长抑制因子ING4在HER2+乳腺癌中异常表达，可能参与疾病的发生和发展。抗HER2耐药的产生与乳腺癌干细胞和相关转录因子有关。NF-κB是调控乳腺癌干细胞和抗HER2耐药的关键转录因子，而ING4对NF-κB有独特的抑制作用。我们预实验发现ING4对HER2+乳腺癌干细胞和抗HER2耐药相关细胞因子有抑制作用。因而推测HER2+乳腺癌ING4异常引起的NF-κB激活可能影响乳腺癌干细胞和介导炎症循环，从而诱发抗HER2原发和继发耐药。本项目将建立HER2+乳腺癌抗HER2原发和继发耐药细胞模型，通过体外和动物体内实验探索ING4在抗HER2耐药产生中的作用及其分子机制，并循证HER2+乳腺癌ING4异常与乳腺癌干细胞、抗HER2疗效和患者预后的相关性，为HER2+乳腺癌患者克服抗HER2耐药提供有价值的实验依据。

The de novo and acquired resistance of anti-HER2 targeted therapy is currently one of major obstacles in HER2+ breast cancer treatment. Inhibitor of growth 4 (ING4) was aberrantly expressed in HER2+ breast cancer, which may be involed in tumorigenesis and development. The anti-HER2 drug resistance is associated with breast cancer stem cells (CSC) and resistance-related transcription factors. It has been reported that NF-κB is a vital transcription factor for breast CSC expansion/maintenance and anti-HER2 drug resistance. It has also been demonstrated that ING4 exhibits unique suppressive activities for NF-κB. Our preliminary data have shown that ING4 inhibits the formation of HER2+ breast cancer stem cells and the secretion of anti-HER2 resistance-associated cytokines. We thus hypothesized that ING4 aberration would result in activation of NF-κB and consequently affect breast CSC in HER2+ breast cancer. Furthermore, NF-κB-mediated inflammatory loop would largely contribute to anti-HER2 de novo and acquired resistance. In the present study, we established HER2+ breast cancer cell model with de novo resistance or de novo sensitivity (that will develop acquired resistance) to anti-HER2 and investigated the effect of ING4 on anti-HER2 resistance and its underlying molecular mechanism in in vitro and in vivo NOD/SCID mouse model. In addition, we explored the clinical correlation of ING4 and HER2+ breast CSC, anti-HER2 therapy efficacy and patient’s prognosis. This project will provide the valuable experimental basis for overcoming anti-HER2 resistance in HER2+ breast cancer patients.