Kumari Kanchan, Kumar Sudarshan, Parida Dillip K, Mishra Sandip K
Cancer Biology Laboratory, Institute of Life Sciences, Department of Biotechnology (Govt. of India), Bhubaneswar, Odisha, India.
Animal Biotechnology Center, National Dairy Research Institute, Karnal, Haryana, India.
Breast Cancer. 2021 Mar;28(2):355-367. doi: 10.1007/s12282-020-01166-0. Epub 2020 Sep 29.
Acquired resistance to drug involves multilayered genetic and epigenetic regulation. Inhibition of EZH2 has proven to reverse the tamoxifen resistance back to the sensitive state in breast cancer. However, the molecular players involved in EZH2-mediated effects on tamoxifen-resistant MCF-7 cells are unknown. This study was conducted to understand the global change in proteome profile of tamoxifen-resistant MCF-7 breast cancer cells upon EZH2 knockdown.
Tamoxifen resistance MCF-7 breast cancer cells were established using increasing concentrations of 4-hydroxy tamoxifen. Using label free proteomics approach, we studied the alteration in total proteome in resistant cells as well as cells transfected with siEZH2 in comparison to sensitive and cells transfected with non-targeting siRNA.
Here, we report list of proteins that were previously not recognized for their role in tamoxifen resistance and hold a close association with breast cancer patient survival. Proteins Annexin A2, CD44, nucleosome assembly protein 1, and lamin A/C were among the most upregulated protein in tamoxifen-resistant cells that were found to be abrogated upon EZH2 knockdown. The study suggests the involvement for various proteins in acquiring resistance towards tamoxifen and anticipates further research for investigating their therapeutic potentials.
Overall, we propose that targeting EZH2 or the molecules down the cascade might be helpful in reacquiring sensitivity to tamoxifen in breast cancer.
获得性耐药涉及多层次的基因和表观遗传调控。已证明抑制EZH2可使乳腺癌中的他莫昔芬耐药逆转至敏感状态。然而，参与EZH2介导的对他莫昔芬耐药的MCF-7细胞作用的分子机制尚不清楚。本研究旨在了解EZH2基因敲低后他莫昔芬耐药的MCF-7乳腺癌细胞蛋白质组图谱的整体变化。
使用浓度递增的4-羟基他莫昔芬建立他莫昔芬耐药的MCF-7乳腺癌细胞系。采用无标记蛋白质组学方法，我们研究了耐药细胞以及转染siEZH2的细胞与敏感细胞和转染非靶向siRNA的细胞相比，总蛋白质组的变化。
在此，我们报告了一些蛋白质的列表，这些蛋白质以前未被认识到在他莫昔芬耐药中的作用，并且与乳腺癌患者的生存密切相关。膜联蛋白A2、CD44、核小体组装蛋白1和核纤层蛋白A/C是他莫昔芬耐药细胞中上调最明显的蛋白质，在EZH2基因敲低后被发现被消除。该研究表明多种蛋白质参与了对他莫昔芬的耐药获得，并期待进一步研究以探究它们的治疗潜力。
总体而言，我们提出靶向EZH2或其下游分子可能有助于恢复乳腺癌对他莫昔芬的敏感性。
