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LncRNA RP11-19E11 is an E2F1 target required for proliferation and survival of basal breast cancer.

ABSTRACT: Long non-coding RNAs (lncRNAs) play key roles in the regulation of breast cancer initiation and progression. LncRNAs are differentially expressed in breast cancer subtypes. Basal-like breast cancers are generally poorly differentiated tumors, are enriched in embryonic stem cell signatures, lack expression of estrogen receptor, progesterone receptor, and HER2 (triple-negative breast cancer), and show activation of proliferation-associated factors. We hypothesized that lncRNAs are key regulators of basal breast cancers. Using The Cancer Genome Atlas, we identified lncRNAs that are overexpressed in basal tumors compared to other breast cancer subtypes and expressed in at least 10% of patients. Remarkably, we identified lncRNAs whose expression correlated with patient prognosis. We then evaluated the function of a subset of lncRNA candidates in the oncogenic process in vitro. Here, we report the identification and characterization of the chromatin-associated lncRNA, RP11-19E11.1, which is upregulated in 40% of basal primary breast cancers. Gene set enrichment analysis in primary tumors and in cell lines uncovered a correlation between RP11-19E11.1 expression level and the E2F oncogenic pathway. We show that this lncRNA is chromatin-associated and an E2F1 target, and its expression is necessary for cancer cell proliferation and survival. Finally, we used lncRNA expression levels as a tool for drug discovery in vitro, identifying protein kinase C (PKC) as a potential therapeutic target for a subset of basal-like breast cancers. Our findings suggest that lncRNA overexpression is clinically relevant. Understanding deregulated lncRNA expression in basal-like breast cancer may lead to potential prognostic and therapeutic applications.

SUBMITTER: Giro-Perafita A

PROVIDER: S-EPMC6944689 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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LncRNA RP11-19E11 is an E2F1 target required for proliferation and survival of basal breast cancer.

Giro-Perafita A A Luo L L Khodadadi-Jamayran A A Thompson M M Akgol Oksuz B B Tsirigos A A Dynlacht B D BD Sánchez I I Esteva F J FJ

NPJ breast cancer 20200106

Long non-coding RNAs (lncRNAs) play key roles in the regulation of breast cancer initiation and progression. LncRNAs are differentially expressed in breast cancer subtypes. Basal-like breast cancers are generally poorly differentiated tumors, are enriched in embryonic stem cell signatures, lack expression of estrogen receptor, progesterone receptor, and HER2 (triple-negative breast cancer), and show activation of proliferation-associated factors. We hypothesized that lncRNAs are key regulators o ...[more]

PMID: 31934613

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Project description:BackgroundPrevious studies have been reported that long non-coding RNA (lncRNA) can regulate the expression of genes which are involved in many important cellular processes The potential role of lncRNA RP11-551L14.4 in the development of breast cancer and the possible regulatory mechanisms was investigated.MethodsQuantitative real-time polymerase chain reaction (qRT-PCR) was conducted to analyze RP11-551L14.4 expression in 36 paired breast cancer tissues and adjacent tissues. The expression of RP11-551L14.4 in multiple breast cancer cell lines was detected by qRT-PCR. Meanwhile, overexpression of RP11-551L14.4 models was established using lentivirus in BT474 and T47D breast cancer cells. Cell counting kit-8 (CCK-8), cell colony formation and cell cycle assays were performed to detect the effects of RP11-551L14.4 on the biological function of breast cancer cells. Besides, bioinformatics techniques, dual luciferase reporter gene assay and rescue experiments were used to investigate the potential mechanisms.ResultsRP11-551L14.4 expression was negatively associated with the advanced tumor stage. Breast cancer patients with low RP11-551L14.4 expression manifested a poorer prognosis. The results of qRT-PCR showed that RP11-551L14.4 expression in breast cancer tissues was significantly lower than in adjacent tissues. Meanwhile, overexpression of RP11-551L14.4 significantly decreased the cell proliferation and cell cycle. Bioinformatics technology showed that RP11-551L14.4 could complementarily bind to miR-4472. qRT-PCR results indicated that the expression levels of miR-4472 and RP11-551L14.4 in breast cancer were negatively correlated. Luciferase reporter gene assay showed that miR-4472 remarkably decreased the relative luciferase activity of the wild-type RP11-551L14.4 vector. miR-4472 is a direct target gene of RP11-551L14.4. miR-4472 levels were reduced, and repulsive guidance molecule A (RGMA) mRNA or protein levels were increased after overexpression of RP11-551L14.4 in the breast cancer cells. miR-4472 reversed the effects caused by RP11-551L14.4 in breast cancer cells.ConclusionRP11-551L14.4 expression was remarkably decreased in breast cancer tissues and cells. RP11-551L14.4 may inhibit the malignant progression of breast cancer by regulating miR-4472 expression.

Dataset Information

LncRNA RP11-19E11 is an E2F1 target required for proliferation and survival of basal breast cancer.

Publications

LncRNA RP11-19E11 is an E2F1 target required for proliferation and survival of basal breast cancer.

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