Loss of fibulin-2 expression is associated with breast cancer progression.
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ABSTRACT:
SUBMITTER: Yi CH
PROVIDER: S-EPMC1854949 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Several studies suggest a link between circadian rhythm disturbances and tumorigenesis. However, the association between circadian clock genes and prognosis in breast cancer has not been systematically studied. Therefore, we examined the expression of 17 clock components in tumors from 766 node-negative breast cancer patients that were untreated in both neoadjuvant and adjuvant settings. In addition, their association with metastasis-free survival (MFS) and correlation to clinicopathological parameters were investigated. Aiming to estimate functionality of the clockwork, we studied clock gene expression relationships by correlation analysis. Higher expression of several clock genes (e.g., CLOCK, PER1, PER2, PER3, CRY2, NPAS2 and RORC) was found to be associated with longer MFS in univariate Cox regression analyses (HR<1 and FDR-adjusted P < 0.05). Stratification according to molecular subtype revealed prognostic relevance for PER1, PER3, CRY2 and NFIL3 in the ER+/HER2- subgroup, CLOCK and NPAS2 in the ER-/HER2- subtype, and ARNTL2 in HER2+ breast cancer. In the multivariate Cox model, only PER3 (HR = 0.66; P = 0.016) and RORC (HR = 0.42; P = 0.003) were found to be associated with survival outcome independent of established clinicopathological parameters. Pairwise correlations between functionally-related clock genes (e.g., PER2-PER3 and CRY2-PER3) were stronger in ER+, HER2- and low-grade carcinomas; whereas, weaker correlation coefficients were observed in ER- and HER2+ tumors, high-grade tumors and tumors that progressed to metastatic disease. In conclusion, loss of clock genes is associated with worse prognosis in breast cancer. Coordinated co-expression of clock genes, indicative of a functional circadian clock, is maintained in ER+, HER2-, low grade and non-metastasizing tumors but is compromised in more aggressive carcinomas.
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Project description:Stromal elastosis is related to good prognosis in breast cancer and fibulin-2 helps to stabilize elastic fibers in basement membranes. Here, we examined the level of perivascular fibulin-2 expression in relation to elastosis content, vascular invasion, molecular subtypes, tumour detection mode, and patient prognosis in breast cancer. We performed a population based retrospective study of invasive breast cancers from the Norwegian Breast Screening Program (Vestfold County, 2004-2009) including 200 screen-detected and 82 interval cancers. Perivascular fibulin-2 staining was semi-quantitatively graded based on immunohistochemistry (1-3) and dichotomized as high expression (grade 2-3) and low expression (grade 1). Elastosis content was graded on a 4-tiered scale and dichotomized as high (score 3) and low (score 0-2) expression, whereas lymphatic (LVI) and blood vessel invasion (BVI) were recorded as absent or present by immunohistochemistry. High perivascular fibulin-2 expression was strongly related to stromal elastosis (p<0.001), and inversely associated with BVI and LVI (p<0.001 for both). High fibulin-2 was associated with luminal breast cancer subgroups (p<0.001) and inversely with interval cancers compared with screen-detected tumours (p<0.001). By univariate analysis, low perivascular fibulin-2 was associated with reduced recurrence-free survival (p = 0.002) and disease specific survival (p = 0.019). Low perivascular fibulin-2 expression was strongly related to vascular invasion, low stromal elastosis, non-luminal breast cancer subtypes, interval presentation, and adverse prognosis.
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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:Fibulin-1, a component of the extracellular matrix (ECM), its prognostic, pathophysiologic and diagnostic role in hepatocellular carcinoma (HCC) is still unexplored. We first found that either Fibulin-1 messenger RNA (mRNA) or protein level was highly elevated in HCC tissues compared with normal tissues. Fibulin-1 correlated with poor overall survival, and it was an independent prognostic predictor (p = 0.001). Furthermore, Overexpression or inhibition of Fibulin-1 reduced or sensitized HCC cells to apoptotic signals, and Fibulin-1 silencing suppressed the ability of HCC cells to form tumors in vivo. Moreover, Fibulin-1 inhibited apoptosis via the Notch pathway while Fibulin-1 silencing had no obvious effect on p-MAPK, p-c-jun and p-stat3 expression, and both Mcl-1 and Bcl-xL are targets of Fibulin-1. Furthermore, the stromal and immune score was elevated in high Fibulin-1 tissues, and FBLN1 expression was associated with increased infiltrating macrophages using xCell, TIMER and TISDIB tool based on TCGA HCC database. Importantly, the circulating cell-free RNA (cfRNA) level of Fibulin-1 in the serum were significantly increased in patients with HCC compared with those in healthy controls, individuals with chronic hepatitis B and patients with HBV-induced liver cirrhosis. The area under receiver operating characteristic curves (AUC) was 0.791 for Fibulin-1, 0.640 for α-fetoprotein and 0.868 for the combination of the two tumor markers. Our findings indicate that Fibulin-1 may be a potential prognostic indicator, a promising serum biomarker and a therapeutic target in patients with HCC.
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Project description:BACKGROUND: Interleukin-6 (IL-6) binds both the membrane and soluble forms of the IL-6 receptor (sIL-6R), which induces a complex with gp130, and proliferation of tumour cells. The aim of this study is to clarify the relationship between tumoral sIL-6R expression and disease progression in colorectal cancer patients. METHODS: We measured tissue concentrations of sIL-6R in tumour and normal mucosa from 161 colorectal cancer patients undergoing surgery, and in supernatants from colon cancer cell lines. The expression of IL-6, IL-6R and gp130 was evaluated by immunohistochemical analysis. RESULTS: Loss of tumour expression of sIL-6R as defined by sIL-6R Ca/N ratio <1.0 was significantly associated with factors reflecting disease progression, and was an independent prognostic factor not only in all the patients in this study, but also in the patients with curative intent. Colon cancer cell lines produced sIL-6R in vitro, and the production of sIL-6R in cancer cell lines was stimulated by cytokine stimulation. Immunohistochemistry revealed that loss of tumour expression of sIL-6R was significantly inversely correlated with intense IL-6 expression in the cytoplasm of cancer cells. In addition, tumoral IL-1beta expression was significantly correlated with sIL-6R expression. CONCLUSION: Loss of tumour expression of sIL-6R is associated with colorectal cancer disease progression.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer type characterized by rapid metastasis and resistance to chemotherapy, properties that are shared by cancer stem cells (CSCs). In pancreatic cancer, tumor cells which possess the properties of CSCs also phenotypically resemble cells that have undergone epithelial-to-mesenchymal transition or EMT. Disabled-2 (Dab2) is a multifunctional scaffold protein frequently downregulated in cancer that has been linked to the process of EMT. However, the role of Dab2 in pancreatic cancer development and progression remains unclear. Downregulation of Dab2 expression in pancreatic cancer cell lines was found to trigger induction of genes characteristic of EMT and the CSC phenotype, while overexpression of Dab2 in the Panc1 cell line blocked the process of TGFβ-stimulated EMT. In addition, selective inhibition of the TGFβRI/RII receptors was found to reverse genes altered by Dab2 downregulation. Dab2 mRNA expression was found to be decreased in PDAC tumor samples, as compared to levels observed in normal pancreatic tissue. Methylation of the Dab2 gene promoter was demonstrated in Stage I PDAC tumors and in the MiaPaCa2 cell line, suggesting that promoter methylation may silence Dab2 expression early in pancreatic cancer progression. These results suggest that Dab2 may function as a tumor suppressor in pancreatic cancer by modulation of the TGFβ-stimulated EMT and CSC phenotype.
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Project description:Transcription factors critical for the transition of normal breast epithelium to ductal carcinoma in-situ (DCIS) and invasive breast cancer are not clearly defined. Here, we report that the expression of a subset of YAP-activated and YAP-repressed genes in normal mammary and early stage breast cancer cells is dependent on the nuclear co-activator AIB1. Gene expression, sequential ChIP, and ChIP-seq analyses show that AIB1 and YAP converge upon TEAD for transcriptional activation and repression. We find that AIB1-YAP repression of genes at the 1q21.3 locus is mediated by AIB1-dependent recruitment of ANCO1, a tumor suppressor whose expression is progressively lost during breast cancer progression. Reducing ANCO1 reverts AIB1-YAP-dependent repression, increases cell size, and enhances YAP-driven aberrant 3D growth. Loss of endogenous ANCO1 occurs during DCIS xenograft progression, a pattern associated with poor prognosis in human breast cancer. We conclude that increased expression of AIB1-YAP co-activated targets coupled with a loss of normal ANCO1 repression are critical to patterns of gene expression that mediate malignant progression of early stage breast cancer.
| S-SCDT-EMBOR-2019-48741-T | biostudies-other