Abstract
BackgroundInflammation is a major player in breast cancer (BC) progression. Allograft-inflammatory factor-1 (AIF1) is a crucial mediator in the inflammatory response. AIF1 reportedly plays a role in BC, but the mechanism remains to be elucidated. We identified two AIF1 isoforms, AIF1v1 and AIF1v3, which were differentially expressed between affected and unaffected sisters from families with high risk of BC with no deleterious BRCA1/BRCA2 mutations (BRCAX). We investigated potential functions of AIFv1/v3 in BC of varying severity and breast adipose tissue by evaluating their expression, and association with metabolic and clinical parameters of BC patients.MethodsAIF1v1/v3 expression was determined in BC tissues and cell lines using quantitative real-time PCR. Potential roles and mechanisms were examined in the microenvironment (fibroblasts, adipose tissue, monocytes and macrophages), inflammatory response (cell reaction in BC subgroups), and metabolism [treatment with docosahexaenoic acid (DHA)]. Association of AIF1 transcript expression with clinical factors was determined by Spearman’s rank correlation. Bioinformatics analyses were performed to characterize transcripts.ResultsAIF1v1/v3 were mostly expressed in the less severe BC samples, and their expression appeared to originate from the tumor microenvironment. AIF1 isoforms had different expression rates and sources in breast adipose tissue; lymphocytes mostly expressed AIF1v1 while activated macrophages mainly expressed AIF1v3. Bioinformatics analysis revealed major structural differences suggesting distinct functions in BC progression. Lymphocytes were the most infiltrating cells in breast tumors and their number correlated with AIF1v1 adipose expression. Furthermore, DHA supplementation significantly lowered the expression of AIF1 isoforms in BRCAX cell lines. Finally, the expression of AIF1 isoforms in BC and breast adipose tissue correlated with clinical parameters of BC patients.ConclusionsResults strongly suggest that AIF1v1 as much as AIF1v3 play a major role in the crosstalk between BC and infiltrating immune cells mediating tumor progression, implying their high potential as target molecules for BC diagnostic, prognostication and treatment.
Highlights
Inflammation is a major player in breast cancer (BC) progression
Patients and study design BRCAX population: Allograft-inflammatory factor-1 (AIF1) As part of a previous study, 115 women issued from BRCA1, BRCA2 and non-BRCA1/2 (BRCAX) families with high risk of BC were selected for transcriptome analysis
Identification of AIF1 transcripts in BRCAX families with high risk of BC Among a list of significant transcripts generated by RNA-sequencing and statistical analyses [28], specific transcripts were selected and validated by qRT-PCR to confirm their differential expression in BC affected and non-affected individuals in a BRCAX subgroup
Summary
Inflammation is a major player in breast cancer (BC) progression. Allograft-inflammatory factor-1 (AIF1) is a crucial mediator in the inflammatory response. According to the latest statistics, females are more likely to develop breast cancer (BC) than any other cancer. The immune system can either recognize and destroy tumors or promote their growth. Many studies have shown that the immune system is a major player in the cancer cell/tumor microenvironment crosstalk. Several clinical studies have evaluated the prognostic significance of tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) in BC [8, 9]. Inflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα), have been shown to play important roles in the progression of BC [10]
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