文献检索，用中文搜 PubMed

INTRODUCTION

Activating the aryl hydrocarbon receptor upon exposure to environmental pollutants promotes development of breast cancer stem cell (CSCs). BCL-2 family proteins protect cancer cells from the apoptotic effects of chemotherapeutic drugs. However, the crosstalk between AhR and the BCL-2 family in CSC development remains uninvestigated.

OBJECTIVES

This study explored the interaction mechanisms between AhR and BCL-2 in CSC development and chemoresistance.

METHODS

A quantitative proteomic analysis study was performed as a tool for comparative expression analysis of breast cancer cells treated by AhR agonist. The basal and inducible levels of BCL-2, AhR, and CYP1A1 in vitro breast cancer and epithelial cell lines and in vivo mice animal models were determined by RT-PCR, Western blot analysis, immunofluorescence, flow cytometry, silencing of the target, and immunohistochemistry. In addition, an in silico toxicity study was conducted using DEREK software.

RESULTS

Activation of the AhR/CYP1A1 pathway in mice increased EpCAM/CD49f CD61 luminal progenitor-like cells in early tumor formation but not in advanced tumors. In parallel, a chemoproteomic study on breast cancer MCF-7 cells revealed that the BCL-2 protein expression was the most upregulated upon AhR activation. The crosstalk between the AhR and BCL-2 pathways in vitro and in vivo modulated the CSCs features and chemoresistance. Interestingly, inhibition of BCL-2 in mice by venetoclax (VCX) increased EpCAM/CD49f CD61 luminal progenitor-like cells, causing inhibition of epithelial lineage markers, disruption of mammary gland branching and induced the epithelial-mesenchymal transition in mammary epithelial cells (MECs). The combined treatment of VCX and AhR antagonists in mice corrected the abnormal differentiation in MECs and protected mammary gland branching and cell identity.

CONCLUSIONS

This is the first study to report crosstalk between AhR and BCL-2 in breast CSCs and provides the rationale for using a combined treatment of BCL-2 inhibitor and AhR antagonist for more effective cancer prevention and treatment.

INTRODUCTION

OBJECTIVES

This study explored the interaction mechanisms between AhR and BCL-2 in CSC development and chemoresistance.

METHODS

RESULTS

CONCLUSIONS

简介

暴露于环境污染物会激活芳香烃受体，从而促进乳腺癌干细胞（CSC）的发展。BCL-2 家族蛋白可保护癌细胞免受化疗药物的凋亡作用。然而，CSC 发育过程中 AhR 与 BCL-2 家族之间的串扰仍未得到研究。

目的

本研究探讨了 AhR 与 BCL-2 在 CSC 发展和化疗耐药中的相互作用机制。

方法

采用定量蛋白质组学分析研究作为工具，比较 AhR 激动剂处理的乳腺癌细胞的比较表达分析。通过 RT-PCR、Western blot 分析、免疫荧光、流式细胞术、靶向沉默和免疫组织化学测定体外乳腺癌和上皮细胞系以及体内小鼠动物模型中 BCL-2、AhR 和 CYP1A1 的基础和诱导水平。此外，还使用 DEREK 软件进行了计算机毒性研究。

结果

在小鼠中激活 AhR/CYP1A1 途径可增加早期肿瘤形成中的 EpCAM/CD49f CD61 腔前体细胞样细胞，但不会增加晚期肿瘤中的细胞。平行地，对乳腺癌 MCF-7 细胞的化学蛋白质组学研究表明，在 AhR 激活时，BCL-2 蛋白表达是上调最明显的。体外和体内 AhR 和 BCL-2 通路的串扰调节了 CSCs 的特征和化疗耐药性。有趣的是，在小鼠中用 venetoclax (VCX) 抑制 BCL-2 增加了 EpCAM/CD49f CD61 腔前体细胞样细胞，导致上皮谱系标志物的抑制、乳腺分支的破坏和诱导乳腺上皮细胞（MECs）中的上皮-间充质转化。在小鼠中联合使用 VCX 和 AhR 拮抗剂的治疗纠正了 MECs 的异常分化，并保护了乳腺分支和细胞特性。