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.

中文翻译：

---

他莫昔芬激活依赖Nrf2的SQSTM1转录以促进子宫内膜增生

通常建议激素受体阳性的乳腺癌患者长期服用他莫昔芬（TAM）。不幸的是，TAM不可避免地会增加子宫内膜增生甚至子宫内膜癌的发生率。尽管进行了大量研究，但尚未认识到预防TAM诱导的子宫内膜癌发生的有效方法。在这项研究中，我们发现抑制Nrf2对预防TAM诱导的子宫内膜增生可能很有价值。经过TAM处理后，自噬衔接子SQSTM1的mRNA和蛋白表达在子宫内膜细胞中特异性增加，而在乳腺癌细胞中则没有。敲低SQSTM1表达可抑制TAM促进子宫内膜癌细胞的生长。TAM通过增强Nrf2的磷酸化和核易位，特别刺激子宫内膜细胞中的SQSTM1转录。实际上，Nrf2和SQSTM1的表达在原发性子宫内膜组织中呈正相关。在TAM诱导的子宫内膜增生的大鼠中，Nrf2和SQSTM1的表达均增加。Nrf2抑制剂Brusatol可有效减轻TAM诱导的SQSTM1上调和子宫内膜增生。Nrf2的激酶PRKCD被TAM激活。PRKCD耗尽后，TAM无法促进Nrf2磷酸化和SQSTM1表达。总之，TAM通过激活PRKCD刺激依赖Nrf2的SQSTM1转录来促进子宫内膜增生。因此，阻断PRKCD-Nrf2-SQSTM1信号传导可能有助于预防TAM诱导的子宫内膜增生。Nrf2和SQSTM1的表达在原发性子宫内膜组织中呈正相关。在TAM诱导的子宫内膜增生的大鼠中，Nrf2和SQSTM1的表达均增加。Nrf2抑制剂Brusatol可有效减轻TAM诱导的SQSTM1上调和子宫内膜增生。Nrf2的激酶PRKCD被TAM激活。PRKCD耗尽后，TAM无法促进Nrf2磷酸化和SQSTM1表达。总之，TAM通过激活PRKCD刺激依赖Nrf2的SQSTM1转录来促进子宫内膜增生。因此，阻断PRKCD-Nrf2-SQSTM1信号传导可能对预防TAM诱导的子宫内膜增生有用。Nrf2和SQSTM1的表达在原发性子宫内膜组织中呈正相关。在TAM诱导的子宫内膜增生的大鼠中，Nrf2和SQSTM1的表达均增加。Nrf2抑制剂Brusatol可有效减轻TAM诱导的SQSTM1上调和子宫内膜增生。Nrf2的激酶PRKCD被TAM激活。PRKCD耗尽后，TAM无法促进Nrf2磷酸化和SQSTM1表达。总之，TAM通过激活PRKCD刺激依赖Nrf2的SQSTM1转录来促进子宫内膜增生。因此，阻断PRKCD-Nrf2-SQSTM1信号传导可能对预防TAM诱导的子宫内膜增生有用。Nrf2抑制剂Brusatol可有效减轻TAM诱导的SQSTM1上调和子宫内膜增生。Nrf2的激酶PRKCD被TAM激活。PRKCD耗尽后，TAM无法促进Nrf2磷酸化和SQSTM1表达。总之，TAM通过激活PRKCD刺激依赖Nrf2的SQSTM1转录来促进子宫内膜增生。因此，阻断PRKCD-Nrf2-SQSTM1信号传导可能对预防TAM诱导的子宫内膜增生有用。Nrf2抑制剂Brusatol可有效减轻TAM诱导的SQSTM1上调和子宫内膜增生。Nrf2的激酶PRKCD被TAM激活。PRKCD耗尽后，TAM无法促进Nrf2磷酸化和SQSTM1表达。总之，TAM通过激活PRKCD刺激依赖Nrf2的SQSTM1转录来促进子宫内膜增生。因此，阻断PRKCD-Nrf2-SQSTM1信号传导可能对预防TAM诱导的子宫内膜增生有用。