Oxidative stress drives endometrial fibrosis via TGF‐β1/MAPK signaling pathway in breast cancer

Hui Chen, Minghua Wang, Zhejun Zhang, Fangfang Lin, Bihui Guo, Qinsheng Lu, Gendie E. Lash, Ping Li
In: The FASEB Journal · 2024 · vol. 38(22) , pp. e70172 · doi:10.1096/fj.202401257rr · PMID:39548950 · W4404436126
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This study found that breast cancer-induced oxidative stress drives endometrial fibrosis through the TGF-β1/MAPK pathway, a process vitamin C can mitigate.

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Abstract

Breast cancer patients have high serum reactive oxygen species (ROS) levels, which exert toxicity on the ovary. However, it is still unclear whether tumor-derived ROS play a role in endometrial development and function in breast cancer. Breast cancer patients and healthy controls were recruited and endometrial thickness was measured by transvaginal ultrasound (TVUS). Xenograft tumors of the breast cancer cell line MDA-MB-231 in a female BALB/c nude mice model were established, and the therapeutic mechanism of vitamin C (VC) was investigated on uterine pathology in vivo and the contribution of co-culture of breast cancer cell and endometrial epithelial cell on this process was examined in vitro. Median thickness in endometria was lower in breast cancer patients and tumor-bearing mice compared to controls. A gene signature of uteri in tumor-bearing mice demonstrated differential expression of genes (DEGs) regulating extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT), and activation of TGF-β and MAPK signaling pathways. In addition, ROS, EMT- and ECM-related protein levels were enhanced in uteri in tumor-bearing mice, as well as in Ishikawa cells which were co-cultured with MDA-MB-231 cells compared to controls. Supplementation with VC reduced endometrial damage, inhibited the EMT process and collagen deposition, and maintained better histologic architecture of uteri in tumor-bearing mice via inactivation of the TGF-β1/p38MAPK pathway. In women with breast cancer oxidative stress in the endometrium results in a fibrotic response as a consequence of EMT. VC could alleviate endometrial fibrosis via TGF-β1/p38MAPK pathway and provide new predictive and therapeutic targets for fertility preservation in younger breast cancer patients.

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