Over-Expression of Centromere Protein U Participates in the Malignant Neoplastic Progression of Breast Cancer.
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ABSTRACT:
SUBMITTER: Hao X
PROVIDER: S-EPMC8021899 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Excess histone deacetylase (HDAC) activity can induce hypoacetylation of histone and nonhistone protein substrates, altering gene expression patterns and cell behavior potentially associated with malignant transformation. However, HDAC expression and protein acetylation have not been studied in the context of breast cancer progression.We assessed expression levels of acetylated histone H4 (ac-H4), ac-H4K12, ac-tubulin, HDAC1, HDAC2, and HDAC6 in 22 reduction mammoplasties and in 58 specimens with synchronous normal epithelium, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) components. Differences among groups were tested for significance using nonparametric tests.From normal epithelium to DCIS, there was a marked reduction in histone acetylation (P < 0.0001). Most cases showed similar levels of acetylation in DCIS and IDC, although some showed further reduction of ac-H4 and ac-H4K12 from DCIS to IDC. Expression of HDAC1, HDAC2, and HDAC6 was also significantly reduced but by a smaller magnitude. Greater reductions of H4 acetylation and HDAC1 levels were observed from normal to DCIS in estrogen receptor-negative compared with estrogen receptor-positive, and in high-grade compared with non-high-grade tumors.Overall, there was a global pattern of hypoacetylation associated with progression from normal to DCIS to IDC. These findings suggest that the reversal of this hypoacetylation in DCIS and IDC could be an early measure of HDAC inhibitor activity.
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Project description:Bladder cancer is one of the most common types of cancer. Most gene mutations related to bladder cancer are dominantly acquired gene mutations and are not inherited. Previous comparative transcriptome analysis of urinary bladder cancer and control samples has revealed a set of genes that may play a role in tumor progression. Here we set out to investigate further the expression of two candidate genes, centromere protein U (CENPU) and mitochondrial ribosomal protein s28 (MRPS28) to better understand their role in bladder cancer pathogenesis. Our results confirmed that CENPU is up-regulated in human bladder cancer tissues at mRNA and protein levels. Gain-of-function and loss-of-function studies in T24 human urinary bladder cancer cell line revealed a hierarchical relationship between CENPU and MRPS28 in the regulation of cell viability, migration and invasion activity. CENPU expression was also up-regulated in in vivo nude mice xenograft model of bladder cancer and mice overexpressing CENPU had significantly higher tumor volume. In summary, our findings identify CENPU and MRPS28 in the molecular pathogenesis of bladder cancer and suggest that CENPU enhances the progression of bladder cancer by promoting MRPS28 expression.
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Project description:Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.
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Project description:BackgroundNeutrophil gelatinase-associated lipocalin (NGAL) has a diverse functional repertoire, involved in the innate immune response as well as cell growth and differentiation. Expression has been linked to malignant disease development and progression.MethodsNeutrophil gelatinase-associated lipocalin expression was assessed immunohistochemically in 98 colorectal neoplastic lesions (52 cancer polyps (CaPs) and 46 sporadic adenoma/adjacent normal mucosa paired specimens) to investigate association with adenoma progression and early colorectal carcinogenesis.ResultsWithin CaPs, all adenomatous and carcinomatous epithelium expressed NGAL, with 92% (43 out of 47) and 58% (19 out of 33) epithelial positivity, respectively, as well as positive stromal cell expression. This was significantly increased compared with normal mucosal epithelium (P=0.0001). Neutrophil gelatinase-associated lipocalin positivity was also identified in sporadic low-grade adenomas, in both the epithelial and stromal compartments as compared with adjacent normal mucosa (P=0.0001 and 0.0002), and this increased along with adenoma size >1 cm (P=0.03).ConclusionNeutrophil gelatinase-associated lipocalin is expressed by the majority of human neoplastic colorectal lesions. This phenotypic switch occurs at an early stage in neoplastic progression with clear differential expression between normal mucosa and adenomatous polyps, rather than further downstream in disease progression at the adenoma-carcinoma transformation. Thus, NGAL expression is not a useful biomarker for determining disease progression from adenomatous to malignant colorectal neoplasia.
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Project description:Gastric cancer (GC) is the 5th most prevalent cancer and the 4th primary cancer-associated mortality globally. As the first identified m6A demethylase for removing RNA methylation modification, fat mass and obesity-associated protein (FTO) plays instrumental roles in cancer development. Therefore, we study the biological functions and oncogenic mechanisms of FTO in GC tumorigenesis and progression. In our study, FTO expression is obviously upregulated in GC tissues and cells. The upregulation of FTO is associated with advanced nerve invasion, tumor size, and LNM, as well as the poor prognosis in GC patients, and promoted GC cell viability, colony formation, migration and invasion. Mechanistically, FTO targeted specificity protein 1 and Aurora Kinase B, resulting in the phosphorylation of ataxia telangiectasia mutated and P38 and dephosphorylation of P53. In conclusion, the m6A demethylase FTO promotes GC tumorigenesis and progression by regulating the SP1-AURKB-ATM pathway, which may highlight the potential of FTO as a diagnostic biomarker for GC patients' therapy response and prognosis.
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Project description:To understand the mechanism underlying metastasis, identification of a mechanism-based and common biomarker for circulating tumour cells (CTCs) in heterogenous breast cancer is needed. SET, an endogenous inhibitor of protein phosphatase 2A, was overexpressed in all subtypes of invasive breast carcinoma tissues. Treatment with SET-targeted siRNAs reduced the motility of MCF-7 and MDA-MB-231 cells in transwell assay. SET knockdown reduced the number of mammospheres by 60-70% in MCF-7 and MDA-MB-231 cells, which was associated with the downregulation of OCT4 and SLUG. Hence, we analysed the presence of SET-expressing CTCs (SET-CTCs) in 24 breast cancer patients. CTCs were enriched using a size-based method and then immunocytochemically analysed using an anti-SET antibody. SET-CTCs were detected in 6/6 (100%) patients with recurrent breast cancer with a median value of 12 (12 cells/3 mL blood), and in 13/18 (72.2%) patients with stage I-III breast cancer with a median value of 2.5, while the median value of healthy controls was 0. Importantly, high numbers of SET-CTCs were correlated with lymph node metastasis in patients with stage I-III disease. Our results indicate that SET contributes to breast cancer progression and can act as a potential biomarker of CTCs for the detection of metastasis.
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Project description:Centromere protein A (CENP-A), an essential centromere protein, has been associated with high grade cancers. This study was undertaken to determine if CENP-A is a prognostic factor for breast cancer patients not receiving systemic therapy or predictive of response to tamoxifen or neoadjuvant chemotherapy.mRNA levels of CENP-A and CENP-B, a centromere protein that binds independently of CENP-A, were measured in breast cancer specimens from 484 patients receiving no systemic therapy, 276 patients receiving tamoxifen, and 233 patients treated with neoadjuvant chemotherapy. Associations between CENP-A, CENP-B, Ki-67, relapse, and chemotherapy response were determined.CENP-A but not CENP-B was higher in estrogen receptor (ER)-negative tumors than ER-positive tumors and positively correlated with Ki-67 expression. Among patients with ER-positive disease who received no systemic therapy or tamoxifen, higher levels of CENP-A were associated with lower rates of 5-year distant relapse free survival (DRFS). On multivariate analyses including Ki-67, high CENP-A expression had a hazard ratio of 10.9 for relapse in patients with ER-positive disease not receiving systemic therapy (95% CI, 2.86 to 41.78; P = 0.00047) and 1.64 for patients with ER-positive disease receiving tamoxifen (95% CI, 0.99 to 2.71; P = 0.054). CENP-A was not an independent prognostic marker in ER-negative tumors. For both ER-positive and ER-negative tumors, CENP-A was not a significant independent predictor of chemotherapy response.CENP-A was a significant independent prognostic marker for patients with ER-positive breast cancer not treated with systemic therapy but had limited predictive value in tamoxifen treated patients and was not predictive of response to neoadjuvant chemotherapy.
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Project description:Increased proliferation and elevated levels of protein synthesis are characteristic of transformed and tumor cells. Though components of the translation machinery are often misregulated in cancers, how tRNA plays a role in cancer cells has not been explored. We compare genome-wide tRNA expression in tumorigenic versus non-tumorigenic breast cell lines, as well as tRNA expression in breast tumors versus normal breast tissues. In tumorigenic versus non-tumorigenic cell lines, nuclear-encoded tRNAs increase by up to 3-fold and mitochondrial-encoded tRNAs increase by up to 5-fold. In tumors versus normal breast tissues, both nuclear and mitochondrial-encoded tRNAs increase by up to 10-fold. This tRNA over-expression is selective and coordinates with the properties of cognate amino acids. Nuclear- and mitochondrial-encoded tRNAs exhibit distinct expression patterns, indicating that tRNAs can be used as biomarkers for breast cancer. We analyzed tRNA expression levels in 2 non-tumorigenic breast cell lines, 6 tumorigenic breast cancer cell lines, 3 normal breast tissue samples, and 9 breast tumor samples. We used a non-tumorigenic breast cell line (MCF10A) as a reference sample in all hybridizations. All data is dye-swapped.
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Project description:The central nervous system (CNS) is a common site of metastatic disease in patients with breast cancer and has few therapeutic options with dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer CNS metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our CNS metastasis cohort. While overall methylation levels were increased in breast cancer CNS metastasis, basal-like CNS metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast CNS metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies. Three sample-types: 35 Breast Brain Metastasis samples, 10 Non-Neoplastic Brain samples, and 10 Non-Neoplastic Breast samples.
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