P110α调控PTEN介导的乳腺癌干细胞从上皮型向间质型转化在乳腺癌转移中的机制研究

Inactivation of the tumor suppressor PTEN was found in over 40% HER2-positive breast cancers and relatived with poor clinical pronogsis and metastasis. Our previous results have indicated that ablation of P110α inhibits metastasis accelerated by loss of PTEN in genetic model and PI3K/AKT signaling pathway including NF-κB and GSK-3β in human breast cancer cells, while the mechanism needs further study. ..New studies suggests that Breast cancer stem cells(BCSCs) exist in distinct mesenchymal-like and epithelial-like states. Mesenchymal-like BCSCs characterized as localized at the tumor invasive front whereas epithelial-like BCSCs are located more centrally. Knocking down PTEN expression lead to expansion of BCSCs population in HER2 overexpressing breast cancer cell lines lead and increased metastasis in mouse xenographs. PTEN deletion also activated NF-κB and GSK-3β participating in epithelial-mesenchymal transition. ..Therefore, we assume that: PTEN deletion promote BCSCs transit from epithelial-like to mesenchymal-like through NF-κB and GSK-3β, while P110α could regulate this transition and metastasis. This paper intends to use gene silencing and specific inhibitor intervention， explore the role of P110α in regulation of BCSCs transition from epithelial-like states to mesenchymal-like states mediated by PTEN, as well as in metastasis.. .This study provides a new perspective for the mechanism of breast cancer metastasis, and provides preclinical evidences for using highly specific molecular targeting therapy for HER2 positive and PTEN-loss breast cancer, a particularly aggressive and currently incurable disease.

PTEN突变缺失或失活发生在超过40%的HER2阳性的人乳腺癌中，并和转移密切相关。我们在前期研究中发现，P110α调控因PTEN缺失而加速的乳腺癌的发生发展及转移，但机制尚待进一步研究。PTEN缺失会诱导乳腺癌干细胞（BCSCs）的产生并增加其转移潜能，还能够激活参与上皮间质转化的NF-κB和GSK-3β。最新研究发现BCSCs存在两种表型：侵袭能力较强的间质细胞样型(间质型)和复制能力较强的上皮细胞样型(上皮型)。因此我们假设：PTEN缺失通过NF-κB和 GSK-3β促进BCSCs从上皮型向间质型转化从而加速转移，而P110α能够调控这一过程。本课题组拟应用基因沉默和特异性抑制剂干预，通过体内外实验深入探讨P110α调控PTEN介导的BCSCs表型转化和转移的机制。本研究为乳腺癌转移机制提供新的视角，为临床应用高度特异性的分子靶向药物提供前临床依据。

1.在高达40%的HER2阳性的乳腺癌中发现PTEN突变缺失或失活，并且PTEN缺失和转移密切相关。Muller等研究者已经证实在高表达ErbB2的MMTV-NIC转基因动物模型中特异性敲除PTEN等位基因后，能够显著地提高乳腺癌的发生发展速率，和提高肺转移几率。 PTEN突变缺失或者失活和靶向HER2治疗抵抗密切相关。目前很多以PI3K/Akt信号通路关键分子为靶点的肿瘤治疗策略正在进行前临床和临床研究中，并显示了良好的应用前景。广泛抑制剂因其针对p110所有亚基，脱靶作用显著，细胞的毒性较大而限制了其临床应用。所以更深入地了解PI3K哪个亚基在这种高侵袭力的乳腺癌亚型中起主要介导作用，才能为临床使用高度靶向小分子抑制剂提供前临床依据。我们通过转基因动物模型实验显示，P110α基因而不是P110β基因在HER2转入PTEN基因敲除的乳腺癌的发生发展中起关键作用，特异性靶向P110α能够克服因PTEN基因缺失诱导的HER2靶向治疗（拉帕替尼）的耐药通过对原代培养的细胞系及相应的移植瘤模型，我们明确：P110α特异性剂BYL719抑制HER2阳性PTEN阴性的乳腺癌细胞的生长，并能够增加其对HER2靶向治疗（曲妥珠单抗和拉帕替尼）的敏感性。.2.流行病学调查和荟萃分析发现洋地黄使用和乳腺癌发病风险之间存在一定关联，但现有流行病学证据仍然不确定，仍需要更好的设计研究.3.MicroRNA-323-3p通过调控Smad2和Smad3蛋白的磷酸化、稳定性以及核转位能力，从而抑制Smad2和Smad3蛋白的活性，最终抑制胰腺癌细胞的上皮——间质转化、侵袭和转移。该结果也进一步验证Smad蛋白家族的磷酸化、稳定性以及核转位能力和肿瘤的侵袭及转移有着密切的联系。

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