Abstract
Simple SummaryCancer-associated fibroblasts (CAFs) promote tumor progression and play an important role in evading immune surveillance. The previous study showed that BAG2 could be elevated in cancer associated fibroblasts (CAFs). Here, we evaluated BAG2 expression of CAF and tumor cells and assessed metastasis risk in patients with breast cancer. We found that patients with either BAG2-high or BAG2(+) CAF had significantly worse distant metastasis-free survival than those with BAG2-double negative. Evaluation of BAG2 expression on both CAFs and tumor cells could be helpful to estimate the risk of metastasis in breast cancer. Few studies have examined the role of BAG2 in malignancies. We investigated the prognostic value of BAG2-expression in cancer-associated fibroblasts (CAFs) and tumor cells in predicting metastasis-free survival in patients with breast cancer. Tissue-microarray was constructed using human breast cancer tissues obtained by surgical resection between 1992 and 2015. BAG2 expression was evaluated by immunohistochemistry in CAFs or the tumor cells. BAG2 expression in the CAFs and cytoplasm of tumor cells was classified as positive and negative, and low and high, respectively. BAG2-CAF was evaluated in 310 patients and was positive in 67 (21.6%) patients. Kaplan–Meier plots showed that distant metastasis-free survival (DMFS) was lesser in patients with BAG2(+) CAF than in patients with BAG2(−) CAF (p = 0.039). Additionally, we classified the 310 patients into two groups: 109 in either BAG2-high or BAG2(+) CAF and 201 in BAG2-low and BAG2(−) CAF. DMFS was significantly reduced in patients with either BAG2-high or BAG2(+) CAF than in the patients of the other group (p = 0.005). Multivariable analysis demonstrated that DMFS was prolonged in patients with BAG2(−) CAF or BAG2-low. Evaluation of BAG2 expression on both CAFs and tumor cells could help in determining the risk of metastasis in breast cancer.
Highlights
The Bcl-2 associated athanogene (BAG) family was first reported as a group of proteins that prevented cell death through their interactions with B-cell lymphoma 2 proteins (Bcl2) [1,2]
Our findings suggest that evaluation of BAG2 expression in the tumor stroma in addition to within the tumor cells could contribute to finer stratification of the metastatic risk in patients with breast cancer
A recent study reported that the level of BAG2 protein is increased in fibroblasts that are co-cultured with ovarian cancer and inferred that BAG2 expression in cancer-associated fibroblasts (CAFs) could be associated with tumor progression through multiple cellular processes [11]
Summary
The Bcl-2 associated athanogene (BAG) family was first reported as a group of proteins that prevented cell death through their interactions with B-cell lymphoma 2 proteins (Bcl2) [1,2]. The BAG protein is known as a negative regulator of the chaperone-associated ubiquitin ligase C terminus of Hsc70-interacting protein (CHIP), which participates in ubiquitin-mediated proteasomal degradation of misfolded substrate proteins [4]. BAG2 is known as an Hsp70/Hsc molecular chaperone-interacting group protein [2]. A previous study of cancer cell lines showed that BAG2 overexpression promoted the accumulation of mutant p53 in the nucleus and inhibited the degradation of mutant p53 through E3 ligase mouse double minute 2 homolog (a negative regulator of the p53 tumor suppressor) [7]. Our group showed that BAG2 regulates the dual functions of cathepsin-B, facilitating the progression of triple-negative breast cancer [8]
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