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01.12.2018 | Primary research | Ausgabe 1/2018 Open Access

Cancer Cell International 1/2018

An isoform of AIF1 involved in breast cancer

Zeitschrift:
Cancer Cell International > Ausgabe 1/2018
Autoren:
Ferial Amira Slim, Geneviève Ouellette, Kaoutar Ennour-Idrissi, Simon Jacob, Caroline Diorio, Francine Durocher
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12935-018-0663-3) contains supplementary material, which is available to authorized users.
Ferial Amira Slim and Geneviève Ouellette are equal first authors

Abstract

Background

Inflammation 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.

Methods

AIF1v1/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.

Results

AIF1v1/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.

Conclusions

Results 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.
Zusatzmaterial
Additional file 1: Table S1. Primer sequence and gene description.
Additional file 2: Figure S1. Estimation of inflammation reaction methods. (A) Delimitation of tumor area and estimation of tumor cell percentage (TCP) and tumor stroma percentage (TSP); (B) Scoring of general inflammatory infiltrate at the invasive margin (Klintrup criteria); (C) Representation of inflammatory cell counting at 20× magnification in one random box in the breast tumor (0.018 mm 2).
Additional file 3. Additional methods.
Additional file 4: Figure S2. Validation of AIF1 expression in BRCAX immortalized lymphoblastoid cells (LCLs) by qRT-PCR in (A) affected sister and (B) non-affected sister. A = affected; NA = non-affected.
Additional file 5: Figure S3. Expression of AIF1 in mammary tissue in isoforms (A) AIF1v1 and (B) AIF1v3. ADH = Atypical ductal hyperplasia; DCIS = Ductal carcinoma in situ; IDC = Invasive ductal carcinoma.
Additional file 6: Figure S4. (A) Analysis of cell viability by crystal violet staining was performed on equal numbers of MCF7 breast cancer cells plated in a 12-well cell culture dish. The cells were transfected with (1) MCF7 alone (2) transfection agent (jetPRIME) 3) empty vector (pcDNA3.1 (+)) and (4) pcDNA3.1 (+)-AIF1v1 and let grown for 4 days. The purple color reflects the number of colonies formed after 4 days. A decrease in the number of colonies indicates decreased proliferation or increased cell death in presence of AIF1. (B) Relative expression levels of AIF1v1 mRNA by real-time PCR. The MCF7 cells seeded in 12-well plates were transfected with (1) MCF7 alone (2) transfection agent (jetPRIME) (3) empty vector (pcDNA3.1(+)) and (4) pcDNA3.1(+)-AIF1v1. HPRT1 was used as an internal control.
Additional file 7: Figure S5. Expression of AIF1v1 (A) and AIF1v3 (B) in cancer cell lines.
Additional file 8: Figure S6. Conversion of E1/E2 at different incubation time periods. E1 = Estrone; E2 =  14C-estradiol.
Additional file 9: Figure S7. AIF1v1 (A) and AIF1v3 (B) expression at varying concentrations of EPA/DHA EPA = Eicosapentaenoic acid; DHA = Docosahexaenoic acid.
Additional file 10: Figure S8. Distribution of breast adipose AIF1v1 expression in BC patients diagnosed with various breast tumors: ductal carcinoma in situ (DCIS), luminal A/B (ER+ and/or PR+), HER2+ (ER−/PR−/HER2+) and triple negative (ER−/PR−/HER2).
Literatur
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