ERα通过下调Bmi1表达介导乳腺癌上皮间质转化的机制

Breast cancer is second only to lung cancer as the cause of cancer-related deaths in women, and the vast majority of breast cancer-related deaths involve distant metastasis.Currently, considerable attention is being directed towards epithelial-mesenchymal transformation (EMT) as the probable ?rst step in the complex process of metastasis. In breast cancer, ERα inhibits EMT through suppressing slug and NK-κB, etc. Breast cancer with ERα expression presents epithelial phenotype, low metastasis rate, and contains a relatively small population of breast cancer stem cell population evidenced by low expression of stem cell markers such as Bmi1, CD44. Currently, mechanism of EMT regulation by ERα, especially mechanism of ERα -maintained breast cancer stem cell properties, has not been elucidated. Bmi1 plays an important role in stem cell self-renewal, cell proliferation, tumorigenesis, and is also a key factor in EMT regulation. Bmi-1 promotes EMT in nasopharyngeal cancer, breast cancer and head and neck squamous cell cancer, etc., through inhibiting E-cadherin expression. Bmi1 can regulate cancer cell stemness by suppressing p16INK4a expression during its regulation of EMT. In our previous experiments, we found that ERα could regulate the expression of Bmi1 in breast cancer cells at both mRNA and protein levels, and confirmed that ERα could bind to Bmi1 promoter with ChIP assay. Therefore, we will first study the molecular mechanisms of regulation of Bmi1 by ERα, and then investigate whether ERα regulates EMT and stemness through Bmi1 in breast cancer cell line, and the relationship between their expression and patient's clinical prognosis. Our findings may provide a novel mechanistic insight into how ERα regulates EMT, and will be of great value for developing new biomarkers predictive of prognosis and targeted therapies for breast cancer patients in the future.

乳腺癌转移是其因癌致死最大的原因。而肿瘤发生转移关键第一步可能是发生上皮间质转化（EMT）。ERα能通过slug、NK-κB等抑制乳腺癌的EMT过程。ERα阳性表达者，表现为上皮性表型、低转移能力，并且乳腺癌干细胞数量较少，低表达Bmi1、CD44等干细胞标记物。目前乳腺癌中ERα调控EMT的机制尚未完全阐明。干细胞自我更新因子Bmi1也是调控EMT的一个关键因素。Bmi1能通过抑制E-cadherin表达促进乳腺癌等肿瘤发生EMT，也能通过抑制p16INK4调控肿瘤干细胞干性。我们的前期实验发现在乳腺癌细胞中，ERα能调控Bmi1的表达，并且能结合到Bmi1启动子区。因此，本项目将首先揭示ERα调控Bmi1的分子机制，进而探究ERα是否能通过Bmi1调控乳腺癌EMT和干细胞干性，最终在人乳腺癌中阐明它们的相关性和临床意义。为进一步研究乳腺癌的侵袭和转移机制以及靶向治疗提供新的理论依据。

在人类乳腺癌中，雌激素受体α（ERα）已被证明抑制上皮- 间质转化（EMT）和干性，是肿瘤转移的两个关键因数。然而，这ERα调节EMT和肿瘤细胞干性的基本机制仍然知之甚少。 Bmi1可调控EMT和保持干细胞的自我更新能力，在人类癌症中常见过表达。在本研究中，我们发现乳腺癌细胞中ERα通过转录下调的Bmi1表达，上调上皮标志E-cadherin的表达。此外，过表达ERα抑制迁移，侵袭和EMT乳腺癌细胞。在ERα阴性乳癌细胞中，过表达ERα可显著降低CD44high/CD24low细胞群数量和抑制乳腺球的形成能力。 Bmi的过表达减弱ERα介导对EMT和细胞干性的抑制。免疫组化显示ERα和Bmi1的表达的乳腺癌组织中呈负相关。总之，我们的研究结果表明，ERα通过下调Bmi1进而抑制EMT。