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

• Published in: Breast cancer research : BCR Vol. 22; no. 1; p. 49
• Main Authors: Al-Ansari, Mysoon M, Al-Saif, Maher, Arafah, Maria, Eldali, Abdelmonneim M, Tulbah, Asma, Al-Tweigeri, Taher, Semlali, Abdelhabib, Khabar, Khalid S, Aboussekhra, Abdelilah
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 15.05.2020; BioMed Central; BMC
• Subjects: Antibodies; ATR; AUF-1; Breast cancer; Cancer patients; Cancer-associated fibroblasts; Care and treatment; Cell cycle; Deoxyribonucleic acid; Development and progression; Disease-free survival; DNA; Fibroblasts; Genes; Immunoblotting; Immunohistochemistry; Interleukin 6; Kinases; Medical prognosis; Medical research; Polymerase chain reaction; Prognosis; Protein kinase; Protein kinases; Proteins; Stat3 protein; Statistical analysis; Tumors; United States > US; Germany; Cancer-associated fibroblasts; Breast cancer; AUF-1; Disease-free survival; ATR
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/s13058-020-01289-4

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. 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. 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. ATR downregulation in breast CAFs is frequent, procarcinogenic, and correlated with poor patient survival.