EZH2 knockdown in tamoxifen-resistant MCF-7 cells unravels novel targets for regaining sensitivity towards tamoxifen
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ORIGINAL ARTICLE
EZH2 knockdown in tamoxifen‑resistant MCF‑7 cells unravels novel targets for regaining sensitivity towards tamoxifen Kanchan Kumari1 · Sudarshan Kumar2 · Dillip K. Parida3 · Sandip K. Mishra1 Received: 14 June 2020 / Accepted: 16 September 2020 © The Japanese Breast Cancer Society 2020
Abstract Background 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. Methods 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. Results 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. Conclusion Overall, we propose that targeting EZH2 or the molecules down the cascade might be helpful in reacquiring sensitivity to tamoxifen in breast cancer. Keywords EZH2 · Tamoxifen · Breast cancer
Introduction Resistance to tamoxifen is a major challenge in the treatment of estrogen receptor (ER) positive breast cancer. More than 70% of breast tumors express ER and respond to tamoxifen; however, a gradual resistance is developed towards tamoxifen during the treatment that poses a serious Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12282-020-01166-0) contains supplementary material, which is available to authorized users. * Sandip K. Mishra [email protected] 1
Cancer Biology Laboratory, Institute of Life Sciences, Department of Biotechnology (Govt. of India), Bhubaneswar, Odisha, India
2
Animal Biotechnology Center, National Dairy Research Institute, Karnal, Haryana, India
3
Department of Radiation Oncology, All India Institute of Medical Sciences, Bhubaneswar 751019, India
concern for the continuation of the therapy [1]. Apart from genetic influence, contribution of epigenetic modification in the development of drug resistance is widely accepted [2–5]. Reversing the drug resistance has been investigated using epigenetic strategies [6]. Histone methylation by polycomb group pro
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