High expression of Linc00959 predicts poor prognosis in breast cancer

Breast cancer is the most common malignant tumor among women worldwide [1]. It has become one of the main causes of harm to women’s health in China, and it is increasing year by year. In 2008, GLOBOCA estimated that breast cancer is the most frequent cancer in Chinese women, with an Age Standardised Rate (ASR) of 21.6 cases per 100,000 women, while in 2015 with an ASR 268.6 cases per 100,000 women [2, 3]. Although the prognosis of breast cancer patients has been greatly improved under multidisciplinary treatment, some patients still has local recurrence and even distant metastasis, eventually leading to death.

Since the completion of the human genome project, it has been found that only about 2% of the human genome encodes proteins, while 98% of transcripts are non-coding RNAs [4]. LncRNA are transcripts of more than 200 nucleotides without the protein coding portraiture [5]. In addition to the fact that they are highly deregulated in tumors, lncRNAs have been found to act as tumor suppressors or oncogenes.

Multiple studies revealed that lncRNA is involved in the initiation and progression of breast cancer. The role of lncRNAs in breast cancer is widely studied. For example, growth arrest-specific transcript 5 (GAS5), has also been shown to be expressed at low levels in breast cancer tissues, GAS5’s overexpression in breast cancer cell lines induced apoptosis and suppressed proliferation [6]. Lnc-BM can prognostic the progression of brain metastasis in breast cancer (BCBM) patients and may be a promising therapeutic target for BCBM [7]. Among them, HOX transcriptional antisense RNA (HOTAIR) gene is most closely related to breast cancer. HOTAIR interacts with Polycomb Repressive Complex 2 (PRC2) and is required for PRC2 occupancy and histone H3 lysine-27 trimethylation of HOXD locus [8]. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. Related studies have found that breast cancer patient’s tumor tissue and plasma had high expression of HOTAIR, HOTAIR diagnostic efficacy and specificity is high and can be used as a potential diagnostic marker for breast cancer [9]. These findings suggest that lincRNAs are a new class of potential biomarkers and targets for the treatment of cancer.

Based on recent studies, we used the TCGA lncRNome information as a clinical filter [10] to find several lincRNAs candidates that have cancer-associated genomic alterations and might be correlated with patient survival in breast cancer. The cohort from the study are made of 290 breast cancer patients from Fudan University Shanghai Cancer Center. The research scientists investigated linc00959 in the cohort. In this research, we found that Linc00959 was significantly associated with poor prognosis and represented a new marker of prognosis in breast cancer.

To our knowledge, Linc00959 was reportedly in non-small-cell lung carcinomas and colorectal cancer [12, 13], but was not previously associated with breast cancer. Sun et al. report that Linc00959 knockdown enhanced colon cancer cell proliferation, invasion, and migration; upregulated N-cadherin and vimentin; and downregulated E-cadherin and Caspase-3. LINC00959 overexpression produced the opposite effects [12]. Linc00959 was reportedly downregulated non-small-cell lung carcinomas [13]. In the future we can use it as reference when we dig in for the molecular mechanism. Colorectal cancer (CRC) patients with high LINC00959 levels had better prognoses than those with low levels, suggesting that LINC00959 may be a useful biomarker for CRC diagnosis [12]. In our study the Kaplan–Meier survival curves indicated that the overall survival (OS) and relapse-free survival (RFS) were significantly poor in high Linc00959 expression BC patients. This suggests that Linc00959 may be an independent prognostic marker in breast cancer.

Breast cancer is the most common malignancy tumor in women. About 70% of patients with breast cancer have tumors presenting ER [14]. However, the development of drug resistance in breast cancer cells is the main cause of treatment failure. Endocrine therapy resistance in breast cancer is a major challenge in the treatment of hormone receptor positive breast cancer. Further explorations of the potential biomarkers to predict patient outcome of Tamoxifen-resistance breast cancer cells and target for therapies are urgently needed. Our data showed that Linc00959 expression was correlated with ER status, PR status, Ki67 and HER2 status. Nowadays, many lncRNA which have shown effective prediction ability. For example, lncRNA HOTAIR is directly repressed by ER and its up-regulation promotes ligand-independent ER activities and contributes to tamoxifen resistance [15]. Tumor-intrinsic plasticity of ERα and H3K27me3 can be a hallmark of endocrine therapy resistance in breast cancer and may ultimately be applicable to guide endocrine treatment selection for patients with breast cancer [16]. Wang et al. [17] developed and validated a novel prognostic tool based on 11-lncRNAs to improve the prediction of disease recurrence for ER-positive BC patients who were treated with tamoxifen as unique endocrine therapy and it can successfully classify patients into high-risk and low-risk groups. The recent active hot spots had focused on lncRNAs can serve as miRNA sponges by competitively binding to miRNA response elements to suppress their expression and function [18]. According Jiang et al. [19] they integrated miRNA–lncRNA signature that can effectively classify TNBC patients into groups with low and high risks of disease recurrence. LncRNA DSCAM-AS1 acts as a competing endogenous RNA of miR-137 and regulates EPS8 to promote cell reproduction and suppresses cell apoptosis in Tamoxifen-resistant breast cancer [20]. As Linc00959 was also associated with ER/PR, we investigated the prognosis of patients treated with tamoxifen. Patients with low Linc00959 expression treated with tamoxifen displayed worse RFS. The results of our study indicate that Linc00959 may represent a new prognostic marker in breast cancer and may be related to endocrine therapy resistance.

The mechanisms accounting for linc00959 associations remain unclear, and further experimental studies were needed to supply the better understanding of linc00959 signature. The next step in-depth study as it may be related to endocrine therapy resistance we can use this as a point cut to investigate thoroughly concrete mechanism of linc00959.

Our studies first uncover the role of a new lincRNA Linc00959 in breast cancer through investigating its expression in a cohort of breast cancer patients and analyzing its correlation with prognosis. The results show that Linc00959 is significantly associated with poor prognosis, especially in ER positive breast cancer treated with tamoxifen and it may represent a new marker of prognosis in breast cancer.