STC2与乳腺癌他莫昔芬内分泌耐药的关系及机制研究

Stanniocalcin 2 (STC2) can regulate breast cancer cell proliferation, apoptosis, invasion and metastasis. However, the relationship between STC2 and endocrine resistance is still unclear. Our previous studies showed that the expression of STC2 is related to Estrogen Receptor (ER), and STC2 can influence Tamoxifen (TAM) sensitivity of breast cancer cells. But the mechanism needs further investigation. Therefore, we put forward the hypothesis that ER expression is down-regulated during the occurrence of TAM resistance in breast cancer cells, leading to down-regulation of STC2 expression and alteration of signaling transduction network related to STC2, thus to changing the phenotype of cell metabolism, and finally resulting in Tamoxifen resistance of breast cancer cells. To test our hypothesis, we will explore the regulation between STC2 and ER, and the role of STC2 in TAM resistance of breast cancer from molecular, cellular, tissue and animal level by establishing TAM-resistant breast cancer cell model and by constructing breast cancer cell lines with different STC2 and ER expression, using qPCR, Western Blot, Lentivirus transfection, RNA interference and other experimental means. Our project will confirm the role and mechanism of STC2 during the occurrence of TAM resistance in breast cancer, and finally, to provide new insights to solve the endocrine resistance problem of ER+ breast cancer.

斯钙素2（Stanniocalcin 2, STC2）对乳腺癌细胞增殖、凋亡、侵袭转移都有调节作用，但其与乳腺癌内分泌耐药的关系仍知之甚少。我们的预实验结果提示STC2与雌激素受体（ER）之间存在相互调节关系并能影响乳腺癌细胞系对他莫昔芬（TAM）的敏感性，但机制还有待探讨。据此我们提出假说：乳腺癌细胞产生TAM耐药的过程中ER表达量降低，ER低表达使STC2表达下降并改变下游信号传导，进而改变细胞代谢等表型，最终导致TAM抵抗。为验证这一假说，我们将建立TAM抵抗的细胞模型及构建不同STC2、ER表达状态的细胞系，采用q-PCR、Western Blot、慢病毒转染、RNA干扰、免疫共沉淀等手段，从分子、细胞、组织以及动物水平探讨STC2与ER的调节关系及其与TAM耐药的关系，明确STC2在TAM耐药过程中的作用及其调控机制，为解决ER+乳腺癌内分泌治疗耐药问题提供新的思路。

斯钙素2（Stanniocalcin 2, STC2）对乳腺癌细胞增殖、凋亡、侵袭转移都有调节作用， 但其与乳腺癌内分泌耐药的关系仍知之甚少。本研究发现STC2高表达与多种肿瘤预后较差相关，但STC2高表达提示较好的乳腺癌预后，且与ER状态相关。乳腺癌阻组织芯片结果进一步证实STC2高表达提示良好预后，且STC2与ER、PR相关。同时，我们构建的内分泌耐药细胞株研究数据显示，TAM耐药与STC2表达无明显相关，然而，氟维司群耐药细胞中STC2表达量显著降低，在氟维司群耐药株中再表达STC2能恢复细胞的药物敏感性。此外，在乳腺癌细胞MCF-7、T47D中敲低STC2能降低细胞对氟维司群的敏感性。机制上，STC2能与ER相互结合调节其功能，ER能调节STC2的表达，同时STC2也对ER的转录水平有调节作用，STC2作为雌激素应答基因，对雌激素引起的内分泌反应有重要作用，表现在STC2敲低后雌激素诱导的靶基因如c-MYC, Cyclin D1, PR等表达下调。因此，本研究表明，STC2与ER能相互作用而发挥内分泌反应调节作用，STC2可作为内分泌治疗反应的一个重要指标。