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EZH2 knockdown in tamoxifen-resistant MCF-7 cells unravels novel targets for regaining sensitivity towards tamoxifen

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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.

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Availability of data and materials

The mass spectrometry proteomics data generated during the study have been deposited to the ProteomeXchange Consortium via the PRIDE with an accession id PXD012609.

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Acknowledgements

We acknowledge DBT, Govt. of India and DST, Govt. of India, for funding. We also acknowledge the Director, Institute of Life Sciences, for the core grant as well as his support in the performance of this project.

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Authors and Affiliations

  1. Cancer Biology Laboratory, Institute of Life Sciences, Department of Biotechnology (Govt. of India), Bhubaneswar, Odisha, India

    Kanchan Kumari & Sandip K. Mishra

  2. Animal Biotechnology Center, National Dairy Research Institute, Karnal, Haryana, India

    Sudarshan Kumar

  3. Department of Radiation Oncology, All India Institute of Medical Sciences, Bhubaneswar, 751019, India

    Dillip K. Parida

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The conception and design of the study, or acquisition of data, or analysis and interpretation of data: KK, SK, DKP, and SKM. Drafting the article or revising it critically for important intellectual content: KK and SK. Final approval of the version to be submitted: KK, SK, DKP, and SKM.

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12282_2020_1166_MOESM1_ESM.pdf

Supplementary file1 Figure S1. Pathway analysis of differentially expressed proteins in tamoxifen resistant MCF-7 cells. Figure shows biological process regulating network analysis of total deferentially expressed proteins in tamoxifen resistant MCF-7 breast cancer cells. Edges (connecting line) describes the kappa score, the thicker the line, higher is the confidence of the kappa score (interaction), the threshold used kappa score for the formation of the network is 0.5 which is already too high for any network. Size of the nodes (circles) depicts the number of genes involved in the process and color of the nodes describes the confidence of the corrected P-value identified. Darker the color, more is the confidence of the identified process in the interaction network. Figure S2. Expression of genes encoding differentially expressed proteins in MTR cells that are significantly associated with overall patient survival. Survival curves show the significant association of genes encoding ANO8, PLP2, ARL6IP1, VBP1 and PTMA with breast cancer patient survival as studied using KM plotter database. HR: Hazard Ratio. Figure S3. Survival curves of genes encoding differentially expressed proteins in MTR cells that are not significantly associated with overall patient survival. Graphs show the non-significant association of genes encoding SH3BGRL3, RHOA, PEA15, AK1, HSPA5, FSCN1, OA48, HSPA1L, CP94 and ABRACL. Figure S4. Correlation graphs for expression of genes encoding ANO8, PLP2, ARL6IP1 and VBP1 with ERα expression in primary breast tumor samples. Using MERAV database, correlation for expression of ANO8, PLP2, ARL6IP1 and VBP1 with ERα was calculated as displayed in the graphs. Figure S5. Protein-protein interaction network for differentially expressed proteins in EZH2 knockdown in MTR cells. Differentially over-expressed and down-regulated proteins were used to identify PPI network for biological processes, molecular functions and cellular component analysis. The connection line-width defines the co-expression the interacting partner proteins in the cellular system. Darker the color, more is the confidence of the identified process in the interaction network. Figure S6. EZH2 knockdown increases the sensitivity of tamoxifen resistant cells towards tamoxifen. Line graph shows the percent cell inhibition in siControl and siEZH2 transfected MTR cells. By taking the log concentrations of tamoxifen and the relative percent absorbance values mentioned below the figure were used to calculate the IC50 value for tamoxifen in both the groups. (PDF 9304 kb)

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Kumari, K., Kumar, S., Parida, D.K. et al. EZH2 knockdown in tamoxifen-resistant MCF-7 cells unravels novel targets for regaining sensitivity towards tamoxifen. Breast Cancer 28, 355–367 (2021). https://doi.org/10.1007/s12282-020-01166-0

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