Int J Biol Sci 2021; 17(10):2380-2398. doi:10.7150/ijbs.55453 This issue

Research Paper

Cx43 deficiency confers EMT-mediated tamoxifen resistance to breast cancer via c-Src/PI3K/Akt pathway

Deng-Pan Wu1,2*, Yan Zhou4*, Li-Xiang Hou1*, Xiao-Xiao Zhu1, Wen Yi1, Si-Man Yang3, Tian-Yu Lin1, Jin-Lan Huang1,2, Bei Zhang5, Xiao-Xing Yin1✉

1. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Pharmacy School of Xuzhou Medical University, Xuzhou City, Jiangsu Province, 221004, P.R. China.
2. Department of Pharmacology, Pharmacy School of Xuzhou Medical University, 221004, Xuzhou City, Jiangsu Province, P.R. China.
3. Scientific research center of traditional Chinese medicine, Guangxi University of Chinese Medicine, Nanning City, Guangxi Zhuang Autonomous Region, P.R. China.
4. Clinical Pharmacy, Jingjiang People's Hospital, 214500, Jingjiang City, Jiangsu Province, P.R. China.
5. Department of gynaecology and obstetrics, Xuzhou Central Hospital, 221009, Xuzhou City, Jiangsu Province, P.R. China.
*These authors contributed equally to this work.

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Citation:
Wu DP, Zhou Y, Hou LX, Zhu XX, Yi W, Yang SM, Lin TY, Huang JL, Zhang B, Yin XX. Cx43 deficiency confers EMT-mediated tamoxifen resistance to breast cancer via c-Src/PI3K/Akt pathway. Int J Biol Sci 2021; 17(10):2380-2398. doi:10.7150/ijbs.55453. Available from https://www.ijbs.com/v17p2380.htm

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Abstract

Graphic abstract

Tamoxifen (TAM) resistance has indicated a significant challenge during endocrine therapy for hormone-sensitive breast cancer. Thus, it is significant to elucidate the molecular events endowing TAM resistance to endocrine therapy. In this study, we found that epithelial-mesenchymal transition (EMT) was an important event to confer TAM resistance, and attenuating EMT by elevating connexin (Cx) 43 expression could reverse TAM resistance. Specifically, Cx43 overexpression improved TAM sensitivity, while Cx43 depletion facilitated TAM insensitivity by modulating EMT in T47D TAM-resistant and -sensitive cells, and transplanted xenografts. Importantly, we found a novel reciprocal regulation between Cx43 and c-Src/PI3K/Akt pathway contributing to EMT and TAM resistance in breast cancer. Moreover, we identified that Cx43 deficiency was significantly correlated with poor relapse-free survival in patients undergoing TAM treatment. Therefore, Cx43 represents a prognostic marker and an attractive target for breast cancer treatments. Therapeutic strategies designed to increase or maintain Cx43 function may be beneficial to overcome TAM resistance.

Keywords: Connexin 43, tamoxifen resistance, epithelial-mesenchymal transition, c-Src/PI3K/Akt pathway