br Adjusted OR br Genotype n ERD br
Genotype n (%) ERD
Abbreviations: Del ¼ deletion; ER ¼ estrogen receptor; Ins ¼ insertion; OR ¼ odds ratio; PR ¼ progesterone receptor. aOdds ratios were adjusted for age and age at menarche.
that the transcriptional activity can be affected by rs145204276. Taken together, these findings suggest that rs145204276 del allele might protect against the occurrence of BC.
It is evident that SNP not only in protein-coding genes but also in noncoding RNAs might contribute to an individual’s suscepti-bility to BC. For example, the risk-associated allele of rs661204 and rs78540526 in 11q13 reduced CY7-SE looping between a distal transcriptional enhancer (proteasome core particle subunit beta 4) and the promoter of lncRNAs (Cyclin D1 -upstream intergenic DNA repair 1 and 2).24 Carriers with the AG genotype of rs619586 in lncRNA metastasis associated lung adenocarcinoma transcript 1
(MALAT1) had a decreased risk of BC in a codominant model, dominant mode, and overdominant model, possibly by reducing the expression level of MALAT1.25 These data suggest that the lncRNA-related SNP might affect its expression and eventually in-fluence the risk of BC development.
Growth arrest-specific 5, a downregulated lncRNA in BC, functions as a tumor suppressor by serving as a molecular sponge for micro-(miR)-196a-5p or miR-21.14,15,26 Upregulation of GAS5 can not only attenuate proliferation and promote apoptosis in vivo and in vitro but also increase the chemotherapeutic effect of den-drosomal curcumin in BC cells,14,15,26,27 whereas reduced GAS5
Figure 2 (A) Relative Expression of Long Noncoding RNA (lncRNA) GAS5 in Tissues With Breast Cancer (BC) and Corresponding Nontumor Normal Tissues. (B) Relative Expression of lncRNA GAS5 in BC Patients Carrying rs145204276 Insertion (Ins)/Ins and Ins/Deletion (Del) and Del/Del Genotypes. (C) Relative Expression of lncRNA GAS5 in Normal Controls Carrying rs145204276 Ins/Ins and Ins/Del and Del/Del Genotypes. GAPDH Was Used as an Internal Control. Data Are Presented as Median With Interquartile Range (*P < .05)
GAS5 Indel Polymorphism and Risk of Breast Cancer
Figure 3 (A) Structure and Location of rs145204276 (-/AGGCA) in the Promoter Region of Long Noncoding RNA (lncRNA) GAS5. The rs145204276 Located in the -268 bp Upstream From the Transcriptional Start Site (TSS) of lncRNA GAS5. Underlined Sequence (GCGCGAGGAA) Indicates SP1-Binding Site. The rs145204276 Deletion (Del) But Not Insertion (Ins) Allele Can Bind to SP1. (B) The Fragments Containing rs145204276 Ins or Del Allele Were Inserted Into pGL3-Basic Vector. Empty Plasmid and Recombinant Plasmids Were Transfected Into HEK293, MCF7, MDA-MB-231, T-47D, and A549 Cells. At 24 Hours After Transfection, Relative Luciferase Activity Was Measured Using the Dual Luciferase Reporter Assay. Data Are Presented as Mean ± Standard Error (**P < .01)
Abbreviations: bp ¼ base pairs; HEK293 ¼ human embryonic kidney 293; MCF7 ¼ michigan cancer foundation-7; MDA-MB-231 ¼ human breast carcinoma; pGL3 ¼ promega’s luciferase reporter vector; SP1 ¼ specificity protein 1.
expression suppresses apoptosis induction by chemotherapeutic agents in BC cells.28 In addition to GAS5, the GAS5 hormone response element mimic sequence can also promote BC cell apoptosis.29 Taken together, these findings indicate that GAS5 might be a target for the development of BC therapy.
On the basis of the research background described herein, we hypothesized that lncRNA GAS5-related SNP might be a reason for explaining individual differences to develop BC. Previously, an ins/ del polymorphism rs145204276 in the promoter region of lncRNA GAS5 was shown to be functional and the del allele was associated with an increased risk of hepatocellular carcinoma17 and cervical squamous cell carcinoma.22 In contrast to these results, we found that the rs145204276 del allele was associated with a reduced risk of BC. Our results were consistent with the findings in gastric can-cer,18,19 lung cancer,20 colorectal cancer,21 and osteosarcoma.23 The conflicting results might be explained by the possibility that the susceptibility loci are different in different cancer types. Addition-ally, the rs145204276 and environment factors might interact with each other in the pathogenesis of BC.