Targeting Ribonucleotide Reductase M2 and NF-κB Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer

Molecular Cancer Therapeutics
Khyati N ShahJesika S Faridi

Abstract

Tamoxifen is widely used as an adjuvant therapy for patients with estrogen receptor (ERα)-positive tumors. However, the clinical benefit is often limited because of the emergence of drug resistance. In this study, overexpression of ribonucleotide reductase M2 (RRM2) in MCF-7 breast cancer cells resulted in a reduction in the effectiveness of tamoxifen, through downregulation of ERα66 and upregulation of the 36-kDa variant of ER (ERα36). We identified that NF-κB, HIF1α, and MAPK/JNK are the major pathways that are affected by RRM2 overexpression and result in increased NF-κB activity and increased protein levels of EGFR, HER2, IKKs, Bcl-2, RelB, and p50. RRM2-overexpressing cells also exhibited higher migratory and invasive properties. Through time-lapse microscopy and protein profiling studies of tamoxifen-treated MCF-7 and T-47D cells, we have identified that RRM2, along with other key proteins, is altered during the emergence of acquired tamoxifen resistance. Inhibition of RRM2 using siRRM2 or the ribonucleotide reductase (RR) inhibitor didox not only eradicated and effectively prevented the emergence of tamoxifen-resistant populations but also led to the reversal of many of the proteins altered during the process of acquired...Continue Reading

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Citations

Apr 19, 2018·Journal of Cellular Physiology·Chao LiShujun Xu
Nov 21, 2018·Molecular Carcinogenesis·Wen-Hui LiangZhi-Hui Wang
Jun 10, 2017·Journal of Neuroinflammation·S D BenusaJ L Dupree
Sep 5, 2019·Pharmaceuticals·Michela AspertiMaura Poli
Jul 20, 2019·Molecular Medicine Reports·Xia LiuJianchao Wang
Nov 30, 2019·Journal of Cellular and Molecular Medicine·Shuai HuangJian Wang
Apr 19, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ying Z MazzuPhilip W Kantoff
Nov 24, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Yaqiong ZhanYunqing Qiu
Sep 25, 2018·Journal of Proteomics·Lokesh D NagaprashanthaSharad S Singhal
Feb 5, 2021·Molecular Cancer Therapeutics·Elizabeth A WilsonJesika S Faridi

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