Abstract
BackgroundMost 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.MethodsWe 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.ResultsWe 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.ConclusionATR downregulation in breast CAFs is frequent, procarcinogenic, and correlated with poor patient survival.
Highlights
Most breast cancer-associated fibroblasts (CAFs) are active and important cancer-promoting cells, with significant impact on patient prognosis
We have recently shown that ATR level is lower in cancer-associated fibroblasts as compared to their corresponding tumor counterpart fibroblasts (TCFs), and ATR inhibits the procarcinogenic effects of CAFs in a p53-dependent manner [8]
IL-6 knockdown by specific siRNA in MDA-MB-231 cells suppressed the paracrine suppressive effect of these cells on the expression of ATR in Breast stromal fibroblast (BSF) (Fig. 1b). This indicates that breast cancer cells downregulate ATR in BSFs in an IL-6-dependent manner
Summary
Most breast cancer-associated fibroblasts (CAFs) are active and important cancer-promoting cells, with significant impact on patient prognosis. While preoperative or neoadjuvant chemotherapy is the mainstay therapeutic strategy for locally advanced breast cancer tumors, it allows disappearance of the tumor (pathological complete response: PCR) in only 20–30% of breast cancer cases [1]. Several lines of evidence showed the presence of clear correlation between CAF-related gene signature and clinical outcome of breast cancer patients. These findings suggested an important role of stromal biology in tumor behavior and the consequent patient response to therapy [4]. We have recently shown that ATR level is lower in cancer-associated fibroblasts as compared to their corresponding tumor counterpart fibroblasts (TCFs), and ATR inhibits the procarcinogenic effects of CAFs in a p53-dependent manner [8]
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