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LINC00978 predicts poor prognosis in breast cancer patients.

ABSTRACT: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women worldwide. Long non-coding RNAs (lncRNAs) are a class of non-coding RNAs in the human genome that involves in breast cancer development and progression. Here, we identify a lncRNA, LINC00978, which is upregulated in breast cancer cell lines and tissues compared with corresponding controls. Furthermore, LINC00978 expression is negatively associated with hormone receptor (HR) status in 195 breast cancer patients studied (p?=?0.033). Kaplan-Meier survival analysis shows that patients with high LINC00978 expression have poorer disease-free survival (DFS) than those with low LINC00978 expression (p?=?0.012), and multivariate analysis identifies LINC00978 as an independent prognostic factor in breast cancer (p?=?0.008, hazard ratio [HR]?=?2.270, 95% confidence interval [CI] 1.237-4.165). Our study indicates that LINC00978 may be an oncogene in breast cancer, and can serve as a potential biomarker to predict prognosis in breast cancer patients.

SUBMITTER: Deng LL

PROVIDER: S-EPMC5126584 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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LINC00978 predicts poor prognosis in breast cancer patients.

Deng Lin-Lin LL Chi Ya-Yun YY Liu Lei L Huang Nai-Si NS Wang Lin L Wu Jiong J

Scientific reports 20161129

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women worldwide. Long non-coding RNAs (lncRNAs) are a class of non-coding RNAs in the human genome that involves in breast cancer development and progression. Here, we identify a lncRNA, LINC00978, which is upregulated in breast cancer cell lines and tissues compared with corresponding controls. Furthermore, LINC00978 expression is negatively associated with hormone receptor (HR) status in 195 breas ...[more]

PMID: 27897214

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Project description:BACKGROUND:In breast cancer, activation of bone morphogenetic protein (BMP) signaling and elevated levels of BMP-antagonists have been linked to tumor progression and metastasis. However, the simultaneous upregulation of BMPs and their antagonist, and the fact that both promote tumor aggressiveness seems contradictory and is not fully understood. METHODS:We analyzed the transcriptomes of the metastatic 66cl4 and the non-metastatic 67NR cell lines of the 4T1 mouse mammary tumor model to search for factors that promote metastasis. CRISPR/Cas9 gene editing was used for mechanistic studies in the same cell lines. Furthermore, we analyzed gene expression patterns in human breast cancer biopsies obtained from public datasets to evaluate co-expression and possible relations to clinical outcome. RESULTS:We found that mRNA levels of the BMP-antagonist Grem1, encoding gremlin1, and the ligand Bmp4 were both significantly upregulated in cells and primary tumors of 66cl4 compared to 67NR. Depletion of gremlin1 in 66cl4 could impair metastasis to the lungs in this model. Furthermore, we found that expression of Grem1 correlated with upregulation of several stem cell markers in 66cl4 cells compared to 67NR cells. Both in the mouse model and in patients, expression of GREM1 associated with extracellular matrix organization, and formation, biosynthesis and modification of collagen. Importantly, high expression of GREM1 predicted poor prognosis in estrogen receptor negative breast cancer patients. Analyses of large patient cohorts revealed that amplification of genes encoding BMP-antagonists and elevation of the corresponding transcripts is evident in biopsies from more than half of the patients and much more frequent for the secreted BMP-antagonists than the intracellular inhibitors of SMAD signaling. CONCLUSION:In conclusion, our results show that GREM1 is associated with metastasis and predicts poor prognosis in ER-negative breast cancer patients. Gremlin1 could represent a novel target for therapy.

Project description:BACKGROUND:DNA methylation (DNAm) age was found to be an indicator for all-cause mortality, cancer incidence, and longevity, but no study has involved in the associations of DNAm age with the prognosis of breast cancer. METHODS:We retrieved information of 1076 breast cancer patients from Genomic Data Commons (GDC) data portal on March 30, 2017, including breast cancer DNAm profiling, demographic features, clinicopathological parameters, recurrence, and all-cause fatality. Horvath's method was applied to calculate the DNAm age. Cox proportional hazards regression models were used to test the associations between DNAm age of the cancerous tissues and the prognosis (recurrence of breast cancer and all-cause fatality) with or without adjusting for chronological age and clinicopathological parameters. RESULTS:The DNAm age was markedly decelerated in the patients who were premenopausal, ER or PR negative, HER2-enriched or basal-like than their counterparts. In the first five-year follow-up dataset for survival, every ten-year increase in DNAm age was associated with a 15% decrease in fatality; subjects with DNAm age in the second (HR: 0.52; 95%CI: 0.29-0.92), the third (HR: 0.49; 95%CI: 0.27-0.87) and the fourth quartile (HR: 0.38; 95%CI: 0.20-0.72) had significant longer survival time than those in the first quartile. In the first five-year follow-up dataset for recurrence, every ten-year increase in DNAm age was associated with a 14% decrease of the recurrence; in the categorical analysis, a clear dose-response was shown (P for trend =0.02) and the fourth quartile was associated with a longer recurrence free survival (HR: 0.32; 95%CI: 0.14-0.74). In the full follow-up dataset, similar results were obtained. CONCLUSIONS:DNAm age of breast cancer tissue, which associated with menopausal status and pathological features, was a strong independent predictor of the prognosis. It was suggested that the prognosis of breast cancer was related to intrinsic biological changes and specific molecular targets for treatment of breast cancer may be implicit.

Project description:IntroductionTriple-negative breast cancer (TNBC) is a heterogeneous disease with no definitive prognostic markers. As a major component of tight junctions, claudins (CLDNs) presumably play an important role in carcinogenesis and progression of breast cancer. This study was aimed at determining the relationship between the expression of CLDNs and the clinical outcomes of TNBCs.Materials and methodsThe surgical specimens of primary breast tumors from a consecutive cohort of 173 TNBC patients were retrospectively collected. The membranous expression of CLDN1, CLDN2, CLDN4, and CLDN7 was measured by immunohistochemistry. Then, the associations between CLDN expression, clinicopathological features, and clinical outcomes were assessed.ResultsPositive CLDN1, CLDN2, CLDN4, and CLDN7 membrane expression was detected in 44.5%, 54.9%, 76.9%, and 73.4% of the cohort specimens, respectively. A lack of CLDN1 expression was related to only lymph node metastasis (P?=?0.014). The rate of CLDN4-positive tumors was significantly increased in tumors of a higher grade (P?=?0.003). Importantly, negative CLDN1 expression was associated with worse relapse-free survival (RFS) in both lymph node positive (LN+) and negative (LN-) cases (both P<0.001). Similarly it was also associated with shorter overall survival (OS)(P?=?0.003 in LN+ cases; P?=?0.018 in LN- cases). In the LN+ subgroup, CLDN2-negative cases had a significantly higher risk of recurrence (P?=?0.008). Multivariate analysis revealed that negative CLDN1 expression was an independent prognostic factor for high risk of both recurrence and death (HR 5.529, 95% CI 2.664-11.475, P<0.001; HR 3.459, 95% CI 1.555-7.696, P?=?0.002). However, neither CLDN4 nor CLDN7 expression was associated with survival.ConclusionIn TNBC, the CLDN1-negative phenotype predicts a high risk of recurrence and death. The absence of CLDN1 expression is strongly suggested to be an independent adverse prognostic factor in this heterogeneous subtype of breast cancer.

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LINC00978 predicts poor prognosis in breast cancer patients.

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LINC00978 predicts poor prognosis in breast cancer patients.

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