High AUF1 level in stromal fibroblasts promotes carcinogenesis and chemoresistance and predicts unfavorable prognosis among locally advanced breast cancer patients.

Autor: Al-Tweigeri T; Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia., AlRaouji NN; Department of Molecular Oncology, Cancer Biology and Experimental Therapeutics Section, King Faisal Specialist Hospital and Research Centre, MBC # 03, PO BOX 3354, Riyadh, 11211, Saudi Arabia., Tulbah A; Department of Pathology, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia., Arafah M; Department of Pathology, King Saud University, PO BOX 2925, Riyadh, 11461, Saudi Arabia., Aboussekhra M; Department of Molecular Oncology, Cancer Biology and Experimental Therapeutics Section, King Faisal Specialist Hospital and Research Centre, MBC # 03, PO BOX 3354, Riyadh, 11211, Saudi Arabia., Al-Mohanna F; Department of Comparative Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia., Gad AM; Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia.; Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, 11591, Egypt., Eldali AM; Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia., Elhassan TA; Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia., Aboussekhra A; Department of Molecular Oncology, Cancer Biology and Experimental Therapeutics Section, King Faisal Specialist Hospital and Research Centre, MBC # 03, PO BOX 3354, Riyadh, 11211, Saudi Arabia. aboussekhra@kfshrc.edu.sa.
Jazyk: angličtina
Zdroj: Breast cancer research : BCR [Breast Cancer Res] 2022 Jul 11; Vol. 24 (1), pp. 46. Date of Electronic Publication: 2022 Jul 11.
DOI: 10.1186/s13058-022-01543-x
Abstrakt: Background: Locally advanced breast cancer (LABC), the most aggressive form of the disease, is a serious threat for women's health worldwide. The AU-rich RNA-binding factor 1 (AUF1) promotes the formation of chemo-resistant breast cancer stem cells. Thereby, we investigated the power of AUF1 expression, in both cancer cells and their stromal fibroblasts, as predictive biomarker for LABC patients' clinical outcome following neoadjuvant treatment.
Methods: We have used immunohistochemistry to assess the level of AUF1 on formalin-fixed paraffin-embedded tissues. Immunoblotting was utilized to show the effect of AUF1 ectopic expression in breast stromal fibroblasts on the expression of various genes both in vitro and in orthotopic tumor xenografts. Cytotoxicity was evaluated using the WST1 assay, while a label-free real-time setting using the xCELLigence RTCA technology was utilized to assess the proliferative, migratory and invasive abilities of cells.
Results: We have shown that high AUF1 immunostaining (≥ 10%) in both cancer cells and their adjacent cancer-associated fibroblasts (CAFs) was significantly associated with higher tumor grade. Kaplan-Meier univariate analysis revealed a strong correlation between high AUF1 level in CAFs and poor patient's survival. This correlation was highly significant in patients with triple negative breast cancer, who showed poor disease-free survival (DFS) and overall survival (OS). High expression of AUF1 in CAFs was also associated with poor OS of ER+/Her2- patients. Similarly, AUF1-positive malignant cells tended to be associated with shorter DFS and OS of ER+/Her2+ patients. Interestingly, neoadjuvant therapy downregulated AUF1 to a level lower than 10% in malignant cells in a significant number of patients, which improved both DFS and OS. In addition, ectopic expression of AUF1 in breast fibroblasts activated these cells and enhanced their capacity to promote, in an IL-6-dependent manner, the epithelial-to-mesenchymal transition and stemness processes. Furthermore, these AUF1-expressing cells enhanced the chemoresistance of breast cancer cells and their growth in orthotopic tumor xenografts.
Conclusions: The present findings show that the CAF-activating factor AUF1 has prognostic/predictive value for breast cancer patients and could represent a great therapeutic target in order to improve the precision of cancer treatment.
(© 2022. The Author(s).)
Databáze: MEDLINE
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