Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, China.
Department of Breast Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
Cancer Gene Ther. 2023 May;30(5):647-658. doi: 10.1038/s41417-022-00542-6. Epub 2022 Oct 14.
Chemotherapy can improve the prognosis and overall survival of breast cancer patients, but chemoresistance continues a major problem in clinical. Most breast cancer is estrogen receptor (ER) positive but responds less to neoadjuvant or adjuvant chemotherapy than ER-negative breast cancer. The Nogo-B receptor (NgBR) increases the chemoresistance of ER-positive breast cancer by facilitating oncogene signaling pathways. Here, we further investigated the potential role of NgBR as a novel target to overcome glycolysis-dependent paclitaxel resistance in ER-positive breast cancer. NgBR knockdown inhibited glycolysis and promoted paclitaxel-induced apoptosis by attenuating HIF-1α expression in ER-positive breast cancer cells via NgBR-mediated estrogen receptor alpha (ERα)/hypoxia-inducible factor-1 alpha (HIF-1α) and nuclear factor-kappa B subunit (NF-κB)/HIF-1α signaling pathways. A ChIP assay further confirmed that NgBR overexpression not only facilitates ERα binding to HIF-1α and GLUT1 genes but also promotes HIF-1α binding to GLUT1, HK2, and LDHA genes, which further promotes glycolysis and induces paclitaxel resistance. In conclusion, our study suggests that NgBR expression is essential for maintaining the metabolism and paclitaxel resistance of ER-positive breast cancer, and the NgBR can be a new therapeutic target for improving chemoresistance in ER-positive breast cancer.
化疗可以改善乳腺癌患者的预后和总生存期，但化疗耐药性仍然是临床中的一个主要问题。大多数乳腺癌是雌激素受体 (ER) 阳性的，但对新辅助或辅助化疗的反应不如 ER 阴性乳腺癌。Nogo-B 受体 (NgBR) 通过促进癌基因信号通路增加 ER 阳性乳腺癌的化疗耐药性。在这里，我们进一步研究了 NgBR 作为一种新的靶点的潜在作用，以克服 ER 阳性乳腺癌中依赖糖酵解的紫杉醇耐药性。通过 NgBR 介导的雌激素受体 alpha (ERα)/缺氧诱导因子-1 alpha (HIF-1α) 和核因子-kappa B 亚基 (NF-κB)/HIF-1α信号通路，NgBR 敲低抑制了 ER 阳性乳腺癌细胞中的糖酵解，并促进了紫杉醇诱导的细胞凋亡，从而减弱了 HIF-1α 的表达。ChIP 实验进一步证实，NgBR 的过表达不仅促进了 ERα 与 HIF-1α 和 GLUT1 基因的结合，而且促进了 HIF-1α 与 GLUT1、HK2 和 LDHA 基因的结合，这进一步促进了糖酵解并诱导了紫杉醇耐药性。总之，我们的研究表明，NgBR 的表达对于维持 ER 阳性乳腺癌的代谢和紫杉醇耐药性是必不可少的，并且 NgBR 可以成为提高 ER 阳性乳腺癌化疗耐药性的新治疗靶点。
