Theranostics 2017; 7(7):1890-1900. doi:10.7150/thno.19135

Research Paper

Tamoxifen activates Nrf2-dependent SQSTM1 transcription to promote endometrial hyperplasia

Lifeng Feng1*, Jiaqiu Li2*, Lixian Yang1, Libo Zhu3, Xiufeng Huang3, Shuzheng Zhang4, Likang Luo5, Zhinong Jiang6, Tingting Jiang1, Wenxia Xu1, Xian Wang2, Hongchuan Jin1✉

1. Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang, Sir Run Run Shaw Hospital, Medical school of Zhejiang University;
2. Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical school of Zhejiang University;
3. Department of Gynecology, Women's Hospital, Medical school of Zhejiang University;
4. Department of Gynecology, Xiaoshan Women's Hospital, Hangzhou;
5. Department of Pathology, Xiaoshan Women's Hospital, Hangzhou;
6. Department of Pathology, Sir Run Run Shaw Hospital, Medical school of Zhejiang University.
* Equal contribution

Abstract

Long-term application of Tamoxifen (TAM) is usually recommended for hormone receptor positive breast cancer patients. Unfortunately, TAM will inevitably increase the incidence of endometrial hyperplasia even endometrial cancer. Despite of substantial investigations, no effective approaches to prevent TAM-induced endometrial carcinogenesis have been acknowledged. In this study, we found that inhibition of Nrf2 could be valuable to prevent TAM-induced endometrial hyperplasia. Upon TAM treatment, the mRNA and protein expression of autophagy adaptor SQSTM1 was specifically increased in endometrial cells but not breast cancer cells. Knocking-down of SQSTM1 expression retarded TAM-promoted growth of endometrial cancer cells. TAM stimulated SQSTM1 transcription specifically in endometrial cells by enhancing phosphorylation and nuclear translocation of Nrf2. Indeed, the expression of Nrf2 and SQSTM1 were positively correlated in primary endometrial tissues. In rats with TAM-induced endometrial hyperplasia, both Nrf2 and SQSTM1 expression were increased. Nrf2 inhibitor brusatol effectively attenuated TAM-induced SQSTM1 upregulation and endometrial hyperplasia. The kinase of Nrf2, PRKCD, was activated by TAM. Once PRKCD was depleted, TAM failed to promote Nrf2 phosphorylation and SQSTM1 expression. In summary, TAM stimulated Nrf2-dependent SQSTM1 transcription to promote endometrial hyperplasia by activating PRKCD. Therefore, blocking PRKCD-Nrf2-SQSTM1 signaling could be useful to prevent TAM-induced endometrial hyperplasia.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Feng L, Li J, Yang L, Zhu L, Huang X, Zhang S, Luo L, Jiang Z, Jiang T, Xu W, Wang X, Jin H. Tamoxifen activates Nrf2-dependent SQSTM1 transcription to promote endometrial hyperplasia. Theranostics 2017; 7(7):1890-1900. doi:10.7150/thno.19135. Available from http://www.thno.org/v07p1890.htm