Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and lacks approved specific targeted therapies. One of the major reasons why TNBC is difficult to treat is the high proportion of cancer stem cells within the tumor tissue. Nucleolus is the location of ribosome biogenesis which is frequently overactivated in cancer cells and overactivation of ribosome biogenesis frequently drives the malignant transformation of cancer. Nucleolar and coiled-body phosphoprotein 1 (NOLC1) is a nucleolar protein responsible for nucleolus organization and rRNA synthesis and plays an important role in ribosome biogenesis. However, the correlation of NOLC1 expression with patient prognosis and its value as a therapeutic target have not been evaluated in TNBC. In the current study, based on bioinformatics analysis of the online databases, we found that the expression of NOLC1 was higher in breast cancer tissues than normal tissues, and NOLC1 was expressed at a higher level in TNBC than other subtypes of breast cancer. GSEA analysis revealed that stemness-related pathways were significantly enriched in breast cancer with high NOLC1 gene expression. Further analyses using gene expression profiling interactive analysis 2 (GEPIA2), tumor immune estimation resource (TIMER) and search tool for retrieval of interacting genes/proteins (STRING) demonstrated that NOLC1 was significantly associated with stemness in both all breast cancer and basal-like breast cancer/TNBC patients at both gene and protein levels. Knockdown of NOLC1 by siRNA decreased the protein level of the key stemness regulators MYC and ALDH and inhibited the sphere-forming capacity in TNBC cell line MDA-MB-231. Univariate and multivariate Cox regression analyses demonstrated that NOLC1 was an independent risk factor for overall survival in breast cancer. PrognoScan and Kaplan-Meier plotter analyses revealed that high expression of NOLC1 was associated with poor prognosis in both all breast cancer and TNBC patients. Further immunohistochemical analysis of breast cancer patient samples revealed that TNBC cells had a lower level of NOLC1 in the nucleus compared with non-TNBC cells. These findings suggest that NOLC1 is closely associated with the stemness properties of TNBC and represents a potential therapeutic target for TNBC.
Highlights
Breast cancer is the most commonly diagnosed malignancy worldwide and the leading cause of cancer-related death in women [1]
We found that NOLC1 expression was higher in breast cancer tissues compared with normal tissues in 5 out of the 6 datasets available (Figure 2A)
By analyzing the RNA-seq data of Triple-negative breast cancer (TNBC) and non-TNBC samples from the The Cancer Genome Atlas (TCGA) dataset downloaded from the cBioPortal database, we found significantly higher levels of NOLC1 in TNBC compared with non-TNBC (Figure 2C)
Summary
Breast cancer is the most commonly diagnosed malignancy worldwide and the leading cause of cancer-related death in women [1]. Triple-negative breast cancer (TNBC), which is characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR), and expression/amplification of human epidermal growth factor receptor 2 (HER2), is the most aggressive and difficult-to-treat subtype of breast cancer [2]. TNBC presents high probability of early recurrence and distant metastasis, leading to poor outcomes [3]. Chemotherapy remains the mainstay of systemic therapy for TNBC, while the majority of patients after treatment develop recurrence within 5 years of diagnosis [4, 5]. Novel targeted therapeutic strategies for TNBC including immune checkpoint inhibition, PARP inhibition, and antibody-drug conjugates have shown benefit for some but not all TNBC patients [6]. Targeting CSCs is regarded as a promising therapeutic strategy for TNBC
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