Clinical and functional significance of tumor/stromal ATR expression in breast cancer patients.

Autor: Al-Ansari MM; Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, MBC#03, Riyadh, 11211, Saudi Arabia.; Department of Microbiology, Faculty of Science and Medical Studies, King Saud University, Riyadh, Saudi Arabia., Al-Saif M; Molecular BioMedicine Program, Research Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia., Arafah M; Department of Pathology, King Saud University, PO BOX 2925, Riyadh, 11461, Saudi Arabia., Eldali AM; Department of Biostatistics, Epidemiology and Scientific computing, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia., Tulbah A; Department of Pathology, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia., Al-Tweigeri T; Department of Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia., Semlali A; Groupe de Recherche en Écologie Buccale, Faculté de Médecine Dentaire, Université Laval Québec, Local 1758, 2420 rue de la terrasse, Québec, G1V 0A6, Canada., Khabar KS; Molecular BioMedicine Program, Research Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia., Aboussekhra A; Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, MBC#03, Riyadh, 11211, Saudi Arabia. aboussekhra@kfshrc.edu.sa.
Jazyk: angličtina
Zdroj: Breast cancer research : BCR [Breast Cancer Res] 2020 May 15; Vol. 22 (1), pp. 49. Date of Electronic Publication: 2020 May 15.
DOI: 10.1186/s13058-020-01289-4
Abstrakt: Background: Most breast cancer-associated fibroblasts (CAFs) are active and important cancer-promoting cells, with significant impact on patient prognosis. Therefore, we investigated here the role of the protein kinase ATR in breast stromal fibroblasts in the prognosis of locally advanced breast cancer patients.
Methods: We have used immunohistochemistry to assess the level of ATR in breast cancer tissues and their adjacent normal tissues. Immunoblotting as well as quantitative RT-PCR were utilized to show the role of breast cancer cells and IL-6 as well as AUF-1 in downregulating ATR in breast stromal fibroblasts. Engineered human breast tissue model was also used to show that ATR-deficient breast stromal fibroblasts enhance the growth of breast cancer cells.
Results: We have shown that the protein kinase ATR is downregulated in cancer cells and their neighboring CAFs in breast cancer tissues as compared to their respective adjacent normal tissues. The implication of cancer cells in ATR knockdown in CAFs has been proven in vitro by showing that breast cancer cells downregulate ATR in breast fibroblasts in an IL-6/STAT3-dependent manner and via AUF-1. In another cohort of 103 tumors from locally advanced breast cancer patients, we have shown that absence or reduced ATR expression in tumoral cells and their adjacent stromal fibroblasts is correlated with poor overall survival as well as disease-free survival. Furthermore, ATR expression in CAFs was inversely correlated with tumor recurrence and progression.
Conclusion: ATR downregulation in breast CAFs is frequent, procarcinogenic, and correlated with poor patient survival.
Databáze: MEDLINE
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