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Tumor tissue microRNA expression in association with triple-negative breast cancer outcomes.

ABSTRACT: We evaluated suggested metastasis-related microRNAs (miRNAs) for their associations with disease-free survival (DFS) and overall survival (OS) of triple-negative breast cancer (TNBC). In a cohort of 456 TNBC cases, we systematically evaluated 57 previously reported metastasis-related miRNAs in tumor tissue using the NanoString nCounter assay. Cox regression was applied to evaluate miRNA expression in association with DFS and OS. In vitro assays using the TNBC cell line MDA-MB-231 were also conducted to validate epidemiological study findings. During a median follow-up of 5.3 years, 112 deaths and 97 recurrences were documented. High levels of miR-374b-5p, miR-218-5p, or miR-126-3p, or low levels of miR-27b-3p were independently associated with a favorable TNBC outcome (P < 0.01 for all). A composite score based on the levels of these four miRNAs was associated with DFS, with hazard ratios (95 % confidence interval) of 0.70 (0.43-1.15), 0.51 (0.29-0.90), and 0.18 (0.09-0.37) for the second, third, and fourth compared to the lowest quartile. Incorporating the miRNA score with known TNBC outcome predictors, i.e., age at diagnosis, tumor stage, and basal-like subtype, increased the C-index for predicting DFS from 0.68 to 0.74. Additionally, miR-126-3p was correlated with basal-like breast cancer, and miR-374b-5p modified the therapeutic effects of 5-Fluorouracil and Cyclophosphamide treatments in basal-like breast cancer patients. Restoring miR-126-3p, miR-218-5p, or miR-374b-5p, or inhibiting miR-27b-3p in MDA-MB-231 cells reduced cell proliferation. miR-374b-5p suppressed cell invasion and miR-218-5p inhibited colonization. This study provides strong evidence that the expression levels of miR-374b-5p, miR-27b-3p, miR-126-3p, and miR-218-5p in tumor tissues predict TNBC outcomes.

SUBMITTER: Liu Y

PROVIDER: S-EPMC4484742 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Tumor tissue microRNA expression in association with triple-negative breast cancer outcomes.

Liu Yan Y Cai Qiuyin Q Bao Ping-Ping PP Su Yinghao Y Cai Hui H Wu Jie J Ye Fei F Guo Xingyi X Zheng Wei W Zheng Ying Y Shu Xiao-Ou XO

Breast cancer research and treatment 20150611 1

We evaluated suggested metastasis-related microRNAs (miRNAs) for their associations with disease-free survival (DFS) and overall survival (OS) of triple-negative breast cancer (TNBC). In a cohort of 456 TNBC cases, we systematically evaluated 57 previously reported metastasis-related miRNAs in tumor tissue using the NanoString nCounter assay. Cox regression was applied to evaluate miRNA expression in association with DFS and OS. In vitro assays using the TNBC cell line MDA-MB-231 were also condu ...[more]

PMID: 26062749

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Project description:Obesity is a risk factor for triple-negative breast cancer (TNBC) incidence and poor outcomes, but the underlying molecular biology remains unknown. We previously identified in TNBC cell cultures that expression of epigenetic reader methyl-CpG-binding domain protein 2 (MBD2), specifically the alternative mRNA splicing variant MBD variant 2 (MBD2_v2), is dependent on reactive oxygen species (ROS) and is crucial for maintenance and expansion of cancer stem cell-like cells (CSCs). Because obesity is coupled with inflammation and ROS, we hypothesized that obesity can fuel an increase in MBD2_v2 expression to promote the tumor-initiating CSC phenotype in TNBC cells in vivo. Analysis of TNBC patient datasets revealed associations between high tumor MBD2_v2 expression and high relapse rates and high body mass index (BMI). Stable gene knockdown/overexpression methods were applied to TNBC cell lines to elucidate that MBD2_v2 expression is governed by ROS-dependent expression of serine- and arginine-rich splicing factor 2 (SRSF2). We employed a diet-induced obesity (DIO) mouse model that mimics human obesity to investigate whether obesity causes increased MBD2_v2 expression and increased tumor initiation capacity in inoculated TNBC cell lines. MBD2_v2 and SRSF2 levels were increased in TNBC cell line-derived tumors that formed more frequently in DIO mice relative to tumors in lean control mice. Stable MBD2_v2 overexpression increased the CSC fraction in culture and increased TNBC cell line tumor initiation capacity in vivo. SRSF2 knockdown resulted in decreased MBD2_v2 expression, decreased CSCs in TNBC cell cultures, and hindered tumor formation in vivo. This report describes evidence to support the conclusion that MBD2_v2 expression is induced by obesity and drives TNBC cell tumorigenicity, and thus provides molecular insights into support of the epidemiological evidence that obesity is a risk factor for TNBC. The majority of TNBC patients are obese and rising obesity rates threaten to further increase the burden of obesity-linked cancers, which reinforces the relevance of this report.

Project description:BACKGROUND:MYC is an oncogenic driver of development and progression in triple-negative breast cancer (TNBC). Ornithine decarboxylase, the rate-limiting enzyme in polyamine metabolism, is a transcriptional target of MYC. We therefore hypothesized that a plasma polyamine signature may be predictive of TNBC development and progression. METHODS:Using liquid chromatography mass spectrometry, polyamine levels were determined in plasma samples from newly diagnosed patients with TNBC (n?=?87) and cancer-free controls (n?=?115). Findings were validated in plasma samples from an independent prospective cohort of 54 TNBC, 55 estrogen receptor negative (ER-) and progesterone receptor negative (PR-) and HER2 positive (HER2+), and 73 ER+ case patients, and 30 cancer-free control subjects. Gene expression data and clinical data for 921 and 2359 breast cancer tumors were obtained from The Cancer Genome Atlas repository and the Oncomine database, respectively. Relationships between plasma diacetylspermine (DAS) and tumor spermine synthase (SMS) mRNA expression with metastasis-free survival and overall survival were determined using Cox proportional hazard models; Fisher exact tests were used to assess risk of distant metastasis in relation to tumor SMS mRNA expression. RESULTS:An increase in plasma DAS, a catabolic product of spermine mediated through SMS, was observed in the TNBC subtype of breast cancer. Plasma levels of DAS in TNBC associated with increased risk of metastasis (plasma DAS value ? 1.16, hazard ratio = 3.06, 95% confidence interval [CI] = 1.15 to 8.13, two-sided P = .03). SMS mRNA expression in TNBC tumor tissue was also found to be predictive of poor overall survival (top 25th percentile hazard ratio = 2.06, 95% CI = 1.04 to 4.08, one-sided P = .04) and increased risk of distant metastasis in TNBC (comparison of lowest SMS quartile [reference] to highest SMS quartile relative risk = 1.90, 95% CI?=?0.97 to 4.06, one-sided Fisher exact test P=.03). CONCLUSIONS:Metabolomic profiling identified plasma DAS as a predictive marker for TNBC progression and metastasis.

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Tumor tissue microRNA expression in association with triple-negative breast cancer outcomes.

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Tumor tissue microRNA expression in association with triple-negative breast cancer outcomes.

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