TARBP2-Enhanced Resistance during Tamoxifen Treatment in Breast Cancer.

Ming-Yang Wang,Jie-Ning Li,Pai-Sheng Chen,Yu-Jhen Lyu,Yao-Lung Kuo,Hsin-Yi Huang,Hung-Yu Sun,Bo-Rong Chen,Chiao Lo

doi:10.3390/cancers11020210

Ming-Yang Wang, Jie-Ning Li + Show 7 more

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https://doi.org/10.3390/cancers11020210

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Abstract

Tamoxifen is the most widely used hormone therapy in estrogen receptor-positive (ER+) breast cancer, which accounts for approximately 70% of all breast cancers. Although patients who receive tamoxifen therapy benefit with respect to an improved overall prognosis, resistance and cancer recurrence still occur and remain important clinical challenges. A recent study identified TAR (HIV-1) RNA binding protein 2 (TARBP2) as an oncogene that promotes breast cancer metastasis. In this study, we showed that TARBP2 is overexpressed in hormone therapy-resistant cells and breast cancer tissues, where it enhances tamoxifen resistance. Tamoxifen-induced TARBP2 expression results in the desensitization of ER+ breast cancer cells. Mechanistically, tamoxifen post-transcriptionally stabilizes TARBP2 protein through the downregulation of Merlin, a TARBP2-interacting protein known to enhance its proteasomal degradation. Tamoxifen-induced TARBP2 further stabilizes SOX2 protein to enhance desensitization of breast cancer cells to tamoxifen, while similar to TARBP2, its induction in cancer cells was also observed in metastatic tumor cells. Our results indicate that the TARBP2-SOX2 pathway is upregulated by tamoxifen-mediated Merlin downregulation, which subsequently induces tamoxifen resistance in ER+ breast cancer.

Highlights

Breast cancer is the most common malignancy in women worldwide and treatment failure remains a major challenge
After screening for the expression of miRNA biogenesis factors, we found that only TARBP2 expression was upregulated in tamoxifen-resistant cells (Figure 1A)
2019, 11, 210TARBP2 (Figure 2I,J). These results indicate that the upregulation of TARBP2 confers acquired resistance to tamoxifen in breast cancer cells

Summary

Introduction

Breast cancer is the most common malignancy in women worldwide and treatment failure remains a major challenge. Cancers 2019, 11, 210 facilitates proliferation and tumorigenesis of breast cancer cells, and hormone therapy is the major treatment for ER+ breast cancer patients. Activation of growth factor receptors, such as EGFR and HER2, has been identified in tamoxifen-resistant cells to induce the MAPK and PI3K/Akt signaling pathways and to enhance mitogenic and antiapoptotic effects. This provides resistant cells with a compensatory survival skill that is independent of the ER pathway [10,11]

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