Huaier extract synergizes with tamoxifen to induce autophagy and apoptosis in ER-positive breast cancer cells

Wenwen Qi,Chang Cai,Jinjing Cun,Qifeng Yang,Yaming Li,Shangge Lv,Xiangnan Kong,Xiaoting Wang,Aijun Yin,Xiaolong Wang,Xia Ding,Junfei Chen,Mingjuan Sun,Sumei Gao

doi:10.18632/oncotarget.8303

Wenwen Qi, Chang Cai + Show 12 more

Open Access

https://doi.org/10.18632/oncotarget.8303

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Abstract

Tamoxifen (TAM) is the most widely used endocrine therapy for estrogen receptor (ER)-positive breast cancer patients, but side effects and the gradual development of insensitivity limit its application. We investigated whether Huaier extract, a traditional Chinese medicine, in combination with TAM would improve treatment efficacy in ER-positive breast cancers. MTT, colony formation, and invasion and migration assays revealed that the combined treatment had stronger anticancer effects than either treatment alone. Huaier extract enhanced TAM-induced autophagy, apoptosis, and G0/G1 cell cycle arrest, as measured by acidic vesicular organelle (AVO) staining, TUNEL, flow cytometry, and western blot. Additionally, combined treatment inhibited tumorigenesis and metastasis by suppressing the AKT/mTOR signaling pathway. Huaier extract also enhanced the inhibitory effects of TAM on tumor growth in vivo in a xenograft mouse model. These results show that Huaier extract synergizes with TAM to induce autophagy and apoptosis in ER-positive breast cancer cells by suppressing the AKT/mTOR pathway.

Highlights

Selective estrogen receptor modulators (SERMs) prevent estrogen from binding to estrogen receptors
Our study demonstrates for the first time that Huaier extract synergizes with tamoxifen to induce autophagy and apoptosis in ER-positive breast cancer cells by inhibiting the AKT signaling pathway
The AKT pathway plays a crucial role in breast cancer pathogenesis, and AKT upregulation is associated with more aggressive clinical phenotypes and worse outcomes in endocrine-treated patients [21, 22]

Summary

Introduction

Selective estrogen receptor modulators (SERMs) prevent estrogen from binding to estrogen receptors. The SERM tamoxifen (TAM) has been used as the standard adjuvant endocrine treatment for more than 30 years for all stages of estrogen-dependent breast cancer [1]. A large randomized clinical trial found that 5 years of treatment with TAM reduced the incidence of invasive breast cancer by about 50% in postmenopausal women who were at high risk of BC [2]. Treatment with TAM alone for estrogen-dependent breast cancer during the premenopausal period is associated with an increased risk of blood clots, especially in the lungs and legs [3], stroke [4], cataracts [5], and endometrial and uterine cancers [4, 6]. Patients become insensitive to this treatment after extended TAM administration and experience other side effects. Combination therapy might enhance the effects of TAM in ER-positive BCs and reduce adverse side effects by decreasing the therapeutic dose of TAM [7]

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