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The inhibitory effect of two chemokine decoy receptors (CDRs), DARC and D6, on breast cancer metastasis is mainly due to their ability to sequester pro-malignant chemokines. We hypothesized that genetic variants in the DARC and CCBP2 (encoding D6) genes may be associated with breast cancer progression. In the present study, we evaluated the genetic contributions of DARC and CCBP2 to metastatic potential, indicated by lymph node metastasis (LNM). Ten single-nucleotide polymorphisms (SNPs) (potentially functional SNPs and block-based tagging SNPs) in DARC and CCBP2 were genotyped in 785 breast cancer patients who had negative lymph nodes and 678 patients with positive lymph nodes. Two non-synonymous SNPs, rs12075 (G42D) in DARC and rs2228468 (S373Y) in CCBP2, were observed to be associated with LNM in univariate analysis and remained significant after adjustment for conventional clinical risk factors, with odds ratios (ORs) of 0.54 (95% confidence interval [CI], 0.37 to 0.79) and 0.78 (95% CI, 0.62 to 0.98), respectively. Additional functional experiments revealed that both of these significant SNPs could affect metastasis of breast cancer in xenograft models by differentially altering the chemokine sequestration ability of their corresponding proteins. Furthermore, heterozygous GD genotype of G42D on human erythrocytes had a significantly stronger chemokine sequestration ability than homozygous GG of G42D ex vivo. Our data suggest that the genetic variants in the CDR genes are probably associated with the varied metastatic potential of breast cancer. The underlying mechanism, though it needs to be further investigated, may be that CDR variants could affect the chemokine sequestration ability of CDR proteins. [ABSTRACT FROM AUTHOR]

Toll-like receptor 3 (TLR3) is a receptor recognizing double-stranded RNA (dsRNA) from viruses as well as from lytic mammalian cells. In the present study, we performed a two-stage association study (n = 3,551) and found that the minor alleles of two SNPs (the T-allele of rs5743312 and the T-allele of rs3775296) conferred increased risks of breast cancer incidence. The adjusted odds ratios (ORs) were 2.281 (P = 7.01 × 10−5) and 2.086 (P = 8.69 × 10−5), respectively. Specifically, the susceptibility variants within TLR3 were significantly associated with larger tumor size (adjusted P-values: 0.004 for rs5743312 and 0.004 for rs3775296). Furthermore, we investigated the biological function of the TLR3 protein in breast cancer cell lines. Notably, the stable expression of TLR3 directly inhibited cell proliferation both in vitro and in vivo. We also verified that TLR3 conferred less invasive phenotypes on breast cancer cells by regulating the mRNA expression of a panel of genes. TLR3-mediated inhibition of proliferation was caused by downregulation of the EGFR/PI3K/AKT pathway. In summary, our findings strongly suggest that common genetic changes in the TLR3 gene may influence breast cancer susceptibility and development, and TLR3 plays a negative regulatory role in the initiation and progression of human breast cancer cells, at least in part by downregulating the EGFR/PI3K/AKT pathway. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the most common cancer among women worldwide, and approximately 70% of breast cancers are hormone receptor-positive and express estrogen receptor-α (ERα) or/and progesterone receptor. ERα has been identified to promote the growth of primary breast cancer, however, it can also antagonize signaling pathways that lead to epithelial-mesenchymal transition (EMT), including transforming growth factor-β (TGF-β) signaling. miRNA alteration or dysfunction is involved in cancer development and progression. Although miR-1271 has identified as a tumor suppressor in various cancers, the role of miR-1271 in breast cancer is still limited. Methods: The effect of miR-1271 on breast cancer progression was investigated both in vitro and in vivo. The EMT-related protein expression levels and localization were analyzed by western blotting and immunofluorescence, respectively. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to validate the regulation of ERα-miR-1271-SNAI2 feedback loop. Results: miR-1271 suppresses breast cancer progression and EMT phenotype both in vitro and in vivo by targeting SNAI2. Estrogen reverses TGF-β-induced EMT in a miR-1271 dependent manner. Furthermore, ERα transactivates the miR-1271 expression and is also transcriptionally repressed by SNAI2. Conclusions: Our data uncover the ERα-miR-1271-SNAI2 feedback loop and provide a mechanism to explain the TGF-β network in breast cancer progression. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer among women worldwide. Chemoresistance remains to be a considerable obstacle in breast cancer therapy and it is often involves dysregulation of a variety of microRNAs (miRNAs). miR-485-5p functions as a tumor suppressor in several types of human cancers. However, its role in breast cancer chemosensitivity have not been determined. In the present study, we demonstrated that overexpression of miR-485-5p suppresses breast cancer progression and enhances chemosensitivity both in vitro and in vivo . Further study demonstrated that miR-485-5p directly targeted the 3′-untranslated region of survivin and overexpression of survivin overcomes the miR-485-5p induced effects on breast cancer. In conclusion, our study identified that miR-485-5p suppresses cancer progression and enhances the chemosensitivity by targeting survivin. Targeting survivin by miR-485-5p may provide a potential approach to reverse chemosensitivity in breast cancer cells. [ABSTRACT FROM AUTHOR]

Highlights: [•] FOXD3 is down-regulated in breast cancer tissues. [•] FOXD3 inhibits breast cancer cell proliferation and invasion. [•] FoxD3 deficiency induces epithelial–mesenchymal transition. [ABSTRACT FROM AUTHOR]