Related Experiment Video
Updated: Oct 26, 2025
Author Spotlight: Exploring Salidroside's Molecular Mechanisms in Breast Cancer Treatment
Published on: June 9, 2023
Cx43 deficiency confers EMT-mediated tamoxifen resistance to breast cancer via c-Src/PI3K/Akt pathway
Deng-Pan Wu1,2, Yan Zhou3, Li-Xiang Hou1
1Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Pharmacy School of Xuzhou Medical University, Xuzhou City, Jiangsu Province, 221004, P.R. China.
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.
Insights
Elevating connexin 43 (Cx43) expression can reverse tamoxifen (TAM) resistance in breast cancer by reducing epithelial-mesenchymal transition (EMT). Cx43 deficiency correlates with poor survival in patients treated with TAM, highlighting its potential as a therapeutic target.
Area of Science:
- Oncology
- Cell Biology
- Molecular Medicine
Background:
- Tamoxifen (TAM) resistance is a major obstacle in treating hormone-sensitive breast cancer.
- Understanding the molecular mechanisms driving TAM resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the role of epithelial-mesenchymal transition (EMT) in TAM resistance.
- To explore the potential of connexin 43 (Cx43) as a modulator of EMT and TAM sensitivity.
- To identify novel therapeutic strategies to overcome TAM resistance in breast cancer.
Main Methods:
- Utilized T47D breast cancer cells (TAM-resistant and -sensitive) and transplanted xenografts.
- Manipulated Cx43 expression (overexpression and depletion) to assess its impact on TAM sensitivity and EMT.
- Investigated the molecular interplay between Cx43, EMT, and the c-Src/PI3K/Akt signaling pathway.
- Correlated Cx43 expression with clinical data from patients undergoing TAM treatment.
Main Results:
- Epithelial-mesenchymal transition (EMT) was identified as a key mechanism conferring TAM resistance.
- Increasing Cx43 expression reversed TAM resistance by attenuating EMT.
- Cx43 depletion promoted TAM insensitivity through EMT modulation.
- A reciprocal regulatory relationship between Cx43 and the c-Src/PI3K/Akt pathway in EMT and TAM resistance was discovered.
- Cx43 deficiency significantly correlated with poorer relapse-free survival in TAM-treated patients.
Conclusions:
- Cx43 plays a critical role in regulating EMT and TAM sensitivity in breast cancer.
- Cx43 serves as a prognostic marker for patients receiving TAM therapy.
- Therapeutic interventions aimed at enhancing Cx43 function hold promise for overcoming TAM resistance.
