4582

MUC1

mucin 1, cell surface associated;MUC1;mucin 1, cell surface associated

DF3 antigen|H23 antigen|Medullary cystic kidney disease, autosomal dominant|breast carcinoma-associated antigen DF3|cancer antigen 15-3|carcinoma-associated mucin|episialin|krebs von den Lungen-6|mucin 1, transmembrane|mucin-1|peanut-reactive urinary muci

1q21

protein-coding

Core 2 beta-1,6-N-acetylglucosaminyltransferase (C2GnT) forms an N-acetylglucosamine branch in O-glycans (core 2 O-glycans) of cell surface glycoproteins. C2GnT-expressing bladder tumors acquire highly metastatic phenotypes by surviving longer in host blood circulation. However, the detailed mechanisms underlying this increased survival remain unclear. In this study, we report that the expression of C2GnT in bladder tumors positively correlates with tumor progression and that bladder tumor cell-surface mucin 1 (MUC1) carrying core 2 O-glycans plays an important role in the evasion from natural killer (NK) cell attack. In C2GnT-expressing bladder tumor cells, heavily core 2 O-glycosylated MUC1 carries poly-N-acetyllactosamine in its O-glycans and galectin-3 binds to MUC1 through this poly-N-acetyllactosamine. The binding of galectin-3 to poly-N-acetyllactosamine in MUC1 core 2 O-glycans attenuates the interaction of the tumor cells with NK cells and interferes with the access of tumor necrosis factor-related apoptosis-inducing ligand to the tumor cell surface. These effects of MUC1 carrying core 2 O-glycans on NK cell attack facilitate C2GnT-expressing tumor cells to evade NK cell immunity and survive longer in host blood circulation. We reveal that MUC1 carrying core 2 O-glycans thus functions as a molecular shield against NK cell attack, thereby promoting bladder tumor metastasis.

MUC1 is a transmembrane glycoprotein abundantly expressed on the apical surface of human ductal epithelial cells and over entire cell surface of tumors originating from those cells. It is 300 to 500 nm long and has a rigid, rod-like structure protruding from the cell surface. MUC1 expressed by normal cells has heavily O-glycosylated tandem repeat domain while MUC1 on malignant cells is aberrantly O-glycosylated. Substantially reduced (aberrant) glycosylation of the tandem repeat region of tumor MUC1 results in uncovering of the polypeptide core. This new structural feature may play an important role in the attachment of metastasizing tumor cells to tissues at distant sites. We show that MDA-MB-231 cells attaching to the immobilized extracellular matrix proteins (ECM) are higher MUC1 expressers than those non-attaching and that the attachment is inhibited by the addition of non-glycosylated, MUC1 peptide. This 100 a.a. peptide composed of 5 tandem repeats from the tandem repeat domain mimics the forms of MUC1 found in ascites fluid of cancer patients. We also show that this synthetic form of MUC1 inhibited attachment of breast tumor cells to sections of normal human lung tissue and immobilized ECM. We did not find correlation between the expression of Tn (GalNAc-Ser/Thr) epitope and the ability of tumor cells to adhere to the immobilized ECM. These results indicate that the non-glycosylated form of MUC1 plays a role in the initial attachment of carcinoma cells to tissues at distant sites, which may facilitate establishment of metastatic foci.

MUC1 is aberrantly expressed in greater than 90% of all breast carcinomas, yet its function as a tumor antigen is not fully understood. Recently, studies have shown that MUC1 interacts with beta-catenin, erbB receptors, src, GSK-3beta and protein kinase Cdelta, possibly in a complex that promotes the disassembly of adherens junctions and the invasion of cells. Here we show that the deletion of Muc1 expression from MMTV-Wnt-1 transgenic mice results in a significant increase in the time to mammary gland tumor onset. Analysis of MMTV-Wnt-1 tumors on a wild-type Muc1 background shows a tumor-specific complex formation between Muc1 and beta-catenin that can be observed in both the membrane and the cytoplasm of transformed epithelium. Analysis of primary human adenocarcinomas revealed that this MUC1/beta-catenin interaction occurs in both primary and metastatic tumors, but is dramatically increased in metastatic lesions. Addition of MUC1-cytoplasmic domain peptides to the invasive MDA-MB-468 and MDA-MB-231 cell lines increases their invasive capability, and these peptides colocalize with both beta-catenin and the focal adhesion protein vinculin, primarily at sites of membrane invasion into a collagen matrix. These data indicate a potential mechanism for MUC1 promotion of invasive tumorigenesis in the breast through the modulation of beta-catenin localization and subsequent cytoskeletal dynamics.

MUC1 is a transmembrane molecule characterized by a repeated sequence of 20 amino acid (TAP PAHGVTSAPDTRPAPGS). Abnormal overexpression of MUC1 in cancer cells is thought to contribute to their aggressive growth, but molecular mechanisms associated with this effect are still unclear. Our current study aimed to clarify whether MUC1 expression as recognized by VU-3C6 anti-MUC1 mouse IgG monoclonal antibody (MAb) with a dominant epitope of 12 amino acids: GVTSAPDTRPAP, correlated with aggressive properties of human breast cancer. Immunohistochemical studies of 309 samples of formalin-fixed and paraffin-embedded materials showed no statistical correlation between MUC1 expression and clinicopathological parameters, as well as several breast cancer aggressiveness-related markers. expression or nonexpression of MUC1 in 50 frozen samples, as determined by Western blotting, demonstrated no correlation with aggressive properties of breast cancer. However, samples with one MUC1-positive band more often had lymphatic vessel invasion and lymph node metastasis than those with more than two or three MUC1-positive bands (p<0.014 and p<0.043, respectively). Because VU-3C6 MAb recognizes MUC1 with short branches of O-glycosylated core carbohydrates, we used immunohistological methods to examine Tn antigen (precursor antigen: GalNAcalpha-O-Ser/Thr), Thomsen-Friedenreich (T) antigen, and sialyl-Tn antigen (STn) antigen. We found a strong correlation between expression of MUC1 and Tn antigen (p<0.0006), and samples with Tn antigen expression had more lymphatic metastasis than those with no such expression (p<0.08). We concluded that the lack of polymorphic MUC1 expression with Tn antigen is one characteristic related to aggressive breast cancer.

tumor response to first-line chemotherapy in advanced breast cancer offers prognostic information and may be used as a surrogate marker for evaluating treatment efficacy. With this study we wanted to determine whether changes in circulating serum CA 15-3 levels during chemotherapy provided additional information for prognostic prediction. Serum CA 15-3 was measured at baseline and after 3 and 6 months during anthracycline-based first-line chemotherapy in 526 patients with advanced breast cancer prospectively enrolled in five phase II-III trials. Changes in marker levels were correlated with disease response, time to progression and overall survival. In all, 336 patients attained a disease response. A significant relationship was found between disease response and CA 15-3 variations, although many individual discrepancies were also observed. At the 6-month time point, the median time to progression was 15.3 months in patients with normal marker levels throughout the study, 11.7 months in those with a CA15-3 reduction >25%, 9.6 months in those with elevated baseline CA 15-3 levels which did not change during therapy and 8.6 months in those with increased marker levels (p < 0.001). The median survival was 42.3, 29.7, 28.5, and 24.8 months, respectively (p < 0.002). The prognostic role of changes in CA 15-3 levels was maintained in the patient subset attaining disease response or stabilization to treatment (p < 0.001) and after adjusting for clinical response and major prognostic parameters in the multivariate analysis (p < 0.001). In conclusion, monitoring serum CA 15-3 levels during first-line chemotherapy in advanced breast cancer patients provides prognostic information independently from tumor response.

Aberrant carbohydrate expression frequently occurs in breast cancer and may endow cells with metastatic potential. Here we first studied the relationship between expression of Vicia villosa agglutinin (lectin) (VVA)-binding carbohydrates and aggressive breast cancer. We then investigated the molecular characteristics of these glycoproteins and compared them with those of glycoproteins recognized by the mouse anti-Tn monoclonal antibody (MAb) HB-Tn1. Histochemical studies of samples from 322 cases of invasive ductal carcinoma demonstrated that VVA-binding carbohydrate expression correlated with tumor stage, lymphatic invasion, and lymph node metastasis (p=0.0385, p=0.0019, and p=0.0430. respectively). Western blotting analysis of frozen materials from 39 cases, under denaturing and reducing conditions, revealed that the major cancer cell-specific VVA-binding proteins were molecules of about 30, 33, and >200 kDa. Cases expressing the approximately 33 kDa molecule had significant lymphatic invasion more frequently than did cases not expressing this molecule (p=0.0076). Binding of VVA to the approximately 30 and approximately 33 kDa molecules was completely lost by preincubation of VVA with 1 mM Tn antigen (N-acetylgalactosamine alpha1-O-serine). The VVA-binding molecules appeared to react with VU-3C6 anti-MUC1 MAb. expression of HB-Tn1 in breast cancer cells showed significant correlation with expression of VVA-binding carbohydrate(s) (p<0.0001) but HB-Tn1 reactivity was not clearly related to breast cancer aggressiveness. Because anti-Tn MAbs bound to Tn antigen clusters, we concluded that atypical MUC1 bearing the noncluster form of Tn antigen is implicated in aggressive growth of primary breast cancer cells, particularly in lymphatic metastasis.

OBJECTIVE: We investigated serum levels of CA 15-3, sHER2 and CA 125, and their usefulness in the detection of metastatic disease in breast cancer patients. METHODS: The levels of CA 15-3, sHER2 and CA 125 tumour markers were determined in 60 patients, 40 with localized and 20 with metastatic breast carcinoma. The control group consisted of 10 healthy women. RESULTS: We found that, at the time of diagnosis, serum levels of all three tumour markers were elevated in patients with distant metastases, but of minute importance in the detection of any breast cancer. When the data for the individual markers were combined the overall sensitivity of metastases detection with all three markers improved. In this regard, 90% of patients with distant metastases had an increase in serum level of at least one of tested tumour markers. Similar results were obtained using receiver operating characteristic curve (ROC). Moreover, using ROC we defined cut-off values for metastasis detection for each of the tested markers. CONCLUSION: Our findings indicate that measurement of CA 15-3 serum values in conjunction with sHER2 and CA 15-3 can increase sensitivity in metastasis detection.

Breast cancer (BC) is the most frequent malignant tumor in women worldwide; its recurrence is a result of undetected metastasis present at the time of primary patient treatment. The detection of cell-free RNA in plasma and serum of human subjects has found increasing applications in the field of medical diagnostics.This study aimed at evaluating plasma mammaglobin mRNA as a useful tumor marker for the diagnosis and the detection of metastasis in breast cancer at the time of diagnosis either alone or in combination with conventional serum tumor markers CA15.3 and/or CEA. This study included 40 Egyptian females with primary breast cancer and 25 with different benign breast diseases. The BC group was classified into 24 patients with localized BC and 16 patients with metastases. All patients were subjected to routine laboratory investigations, estimation of serum CA15.3 and CEA by electrochemiluminescence immunoassay and detection of plasma mammaglobin mRNA by using nested reverse transcriptase polymerase chain reaction (RT-PCR). There was a significance increase in plasma mammaglobin mRNA expression, CA15.3 and CEA levels in BC group as compared to benign group (p < 0.001). No significant difference was observed between levels of plasma mammaglobin mRNA expression in patients with tumor's size or grade. No correlation was observed with plasma mammaglobulin mRNA levels and tumor size or grading, CEA and CA15.3. There was a significant difference (p < 0.05) and a positive correlation between CA 15.3 and CEA levels in patients with tumor size and grading. expression of plasma mammaglobin mRNA has the highest sensitivity, specificity and diagnostic accuracy for both BC and BC with metastasis (75%, 92% & 81.5%) and (87.5%, 45.8% & 62.5%), respectively. To improve diagnostic efficacy of BC, the use of combined tests, expression of plasma mammaglobin mRNA and CA 15.3 improved the sensitivity, specificity and diagnostic accuracy to 90%, 80% & 86.2%, respectively; as well as in BC with metastasis to 100%, 79.2%, & 87.5%, respectively. In conclusion, plasma mammaglobin mRNA alone or in combination with CA15.3 may be used as a valuable noninvasive approach for the diagnosis and the detection of metastasis in breast cancer at the time of diagnosis.

INTRODUCTION: Mucin 1 antigen (MUC1) is a high-molecular-weight transmembrane glycoprotein with an aberrant expression profile in various malignancies, including breast cancer. Its increased overexpression and underglycosylation in breast cancer is associated with tumor invasiveness and metastatic potential. In this study, we took the next step toward establishing MUC1 as a potential diagnostic, prognostic, and therapeutic target by investigating its expression and posttranslational modification (glycosylation/sialylation). PATIENTS AND METHODS: In these studies we used a breast cancer tissue microarray (TMA) and fresh-frozen multistage breast cancer tissues. We analyzed in detail the expression of normal and underglycosylated/sialated MUC1 by immunohistochemical techniques, real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), and various analytic techniques. RESULTS: We found that changes in cellular localization as well as in upregulation and/or underglycosylation of MUC1 were associated with higher tumor grade. A key finding in this study was that underglycosylated MUC1 (uMUC1) overexpression and sialation were observed in tissues adjacent to tumor but identified as normal on pathology reports. CONCLUSIONS: These findings suggest that uMUC1 can indeed be used as an early diagnostic marker and provide additional insights into breast cancer management.

OBJECTIVE: To study the correlation between the stromal cell-derived factor (SDF-1) and the receptor fusin (CXCR4) in carcinoma of larynx, and investigate some mechanisms of SDF-1/CXCR4 during the development, invasion and lymph node metastasis of laryngocarcinoma. METHOD: Detecting the expression of SDF-1 and CXCR4 by immunohistochemical method (SP) in laryngocarcinoma, paraneoplastic tissues, normal laryngeal mucosa and cervical lymph node. Using Kruskal-Wallis H test, chi2 test, Spearman rank correlation analysis and so on to do statistical analysis. RESULT: The positive expression rate of SDF-1 and CXCR4 in laryngocarcinoma was obviously higher than in paraneoplastic tissues and normal laryngeal mucosa tissues (P < 0.01). And the expression of two proteins was correlated with lymph node metastasis (P < 0.01), clinical stage (P < 0.01) and pathological grading of tumor (P < 0.05). The positive expression rate of SDF-1 and CXCR4 protein in metastasis lymph node tissue was higher than that in non metastasis lymph node tissue (P < 0.01). The expression of SDF-1 is correlated positively with the expression of CXCR4 in laryngocarcinoma. CONCLUSION: SDF-1 and CXCR4 protein are highly expressed in laryngocarcinoma and in metastasis lymph node tissue. And they are correlated with lymph node metastasis, clinical stage and pathological grading of the tumor. According to the results, the two proteins may relate to infiltration and metastasis of laryngeal squamous cell carcinoma and play a role of synergistic action in the development and invasion of carcinoma of larynx.

The value of serum tumour markers in the prognosis of patients with breast cancer is controversial. This prospective study in Yazd, Islamic Republic of Iran, assessed the value of the tumour markers carcinoembryonic antigen (CEA) and cancer antigen (CA) 15-3 in 159 patients with primary breast cancer. CEA and CA15-3 assays (mean 14 per patient) were performed at diagnosis, end of surgery and chemotherapy and every 3 months in the first 2 years and every 6 months in second 2 years of the follow-up period. During follow-up, 33 patients (20.8%) presented symptomatic metastasis. A significant relationship was seen between metastasis status and positive CEA and CA15-3 levels. The sensitivity and specificity were 66.7% and 98.4% for CEA respectively and 84.8% and 91.3% for CA15-3 respectively. Optimum cut-offs were 4.95 ng/mL and 30.5 U/mL for CEA and CA15-3 respectively.

BACKGROUND: Breast cancer is the second leading cancer causing death in women. Circulating tumor cells are among the prognostic factors while tumor markers are of diagnostic value and can be used for follow-up. The aim of this study was to investigate the correlation between the prognostic significance of the serum CA15-3 levels, number of circulating tumor cells and histopathological tumor factors. MATERIALS AND METHODS: Thirty patients recently diagnosed with breast cancer were included in the study. Number of circulating tumor cells and serum CA15-3 level were assessed when metastasis was detected and diagnostic value was assessed. Presence of associations with estrogen and progesterone receptors, c-erbB2, Ki-67 proliferation index and histological grade were also evaluated. RESULTS: Median overall survival of the patients with serum CA15-3 levels of >108 ng/dl was 19 months whereas for those with a low serum level it was 62 months. Median overall survival for CTC >/=5vs CTC<5 patients was 19 months and 40 months respectively. The difference between the two groups was statistically significant. CONCLUSIONS: Prognostic significance of the CTC count and CA15-3 levels in metastatic breast cancer patients was demonstrated.

To investigate the prognostic value of tumor markers, cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) levels at diagnosis of systemic recurrence. After primary treatments of locoregional breast cancers, serum CA 15-3 and/or CEA concentrations were regularly measured, and systemic recurrences were identified in 351 patients between January 1999 and December 2009. The association between tumor marker levels at systemic recurrence and survival were investigated by univariate and multivariate analyses. Elevated CA 15-3 and CEA levels were identified in 194 of 349 (55.6 %) and 111 of 308 (36.0 %) patients, respectively, at diagnosis of systemic recurrence. Elevated levels of CA 15-3 and CEA were correlated with visceral or multiple recurrences and elevated preoperative levels. Elevation of CA 15-3 was more prominent in younger patients and in primary node-positive tumors, while CEA was elevated in older patients at diagnosis and in estrogen receptor (ER)-positive tumors. Elevated tumor markers as well as ER negativity, short disease-free interval, and advanced stage at initial diagnosis showed independent prognostic significance on multivariate analysis. Among 306 patients for whom levels of both tumor markers at recurrence were available, 106 patients without elevation of either marker showed significantly better overall survival than those with elevated levels of either one or both markers, and the significance persisted in multivariate analysis. Elevated serum CA 15-3 and CEA levels at recurrence suggest increased tumor burden and may be prognostic for survival for metastatic breast cancer patients.

BACKGROUND: The prognostic value of serum tumor markers (STMs) in nonmetastatic breast cancer patients with different molecular subtypes (luminal A, luminal B, and nonluminal) remains unknown. It is our institutional policy to assess the STMs in nonmetastatic patients. This retrospective single-center study is to investigate the association between STMs and clinical outcomes in nonmetastatic patients and the impact of molecular subtypes. METHODS: A total of 368 patients with available clinical outcomes, tumor node metastasis stages, and STMs levels were included. The serum level of preoperative STMs (carcinoembryonic antigen [CEA], cancer antigen 125 [CA-125], and cancer antigen 15-3 [CA 15-3]) was analyzed and compared among distinct molecular subtypes. Univariate and multivariate analyses were used to investigate the relationship among STMs concentrations and patient outcomes. RESULTS: The median levels of CA 15-3 were 10.2, 8.1 and 7.1 U/mL in patients with luminal A, luminal B, and nonluminal diseases, respectively (P = 0.015). The levels of CEA and CA-125 were similar among the subtypes. Multivariate analysis showed that higher CA 15-3 was significantly associated with worse clinical outcomes exclusively in luminal A patients (P = 0.033 for metastasis-free survival and P = 0.030 for relapse-free survival). In contrast, higher CEA was a significant prognostic factor for worse clinical outcomes (P = 0.003 for metastasis-free survival and P = 0.015 for metastasis-free survival) in nonluminal groups. CONCLUSIONS: The prognostic value of preoperative STMs may be different among molecular subtypes. Patients with luminal A diseases had higher levels of CA 15-3. Higher preoperative CA 15-3 was associated with worse clinical outcomes exclusively in patients with luminal A diseases.

PURPOSE: Increasing evidences demonstrate that CD227 plays a crucial role in the development and progression of breast cancer. However, the function of CD227 in breast carcinoma was still controversial and the investigation on CD227 in Asian race was scarce. METHODS: To investigate the relationship between CD227 and tumor characteristics of breast carcinoma, CD227, estrogen receptor (ER), progesterone receptor (PR), Her2neu and Ki-67 were detected by immunohistochemistry in a series of 227 patients. The Kaplan-Meier method and log-rank tests were used to estimate the correlation between CD227 expression and patients' prognosis. Furthermore, in vitro invasion assay was performed to examine the effect of CD227 on the invasiveness of breast carcinoma cells after transfection with CD227 cDNA or antisense phosphorothioate oligodeoxynucleotides (ASODN) against CD227 mRNA. RESULTS: Our data demonstrate that the cytoplasm staining and high expression of CD227 were positively related to the aggressiveness of breast cancer. Both circumferential membrane staining and cytoplasm staining were associated with lymph node metastasis. Moreover, the cytoplasm staining and overexpression of CD227 were found to be related to Her-2/neu positivity, higher Ki-67 positivity and poorer survival of patients. We further demonstrated that the invasion ability of breast carcinoma cells could be enhanced or inhibited by CD227 cDNA or ASODN, respectively. CONCLUSIONS: We conclude that the aberrant expression of CD227, especially cytoplasm staining could be predictive for tumor aggressiveness, lymph node metastasis, poorer outcome of patients with breast cancers. And CD227 could promote the invasion ability of breast cancer cells, suggesting a potential role of CD227 as an oncogene in breast carcinoma.

Endometrial cancer is the most common malignancy of the female genital tract and is associated with poor prognosis. It is primarily a hormone-dependent cancer that is regulated by steroid hormones, including estrogen and progesterone. Forkhead box A1 (FOXA1) is a member of the forkhead box transcription factor family and functions as a pioneer factor in estrogen receptor (ER)-positive breast cancer. In the present study, we investigated the expression of FOXA1 in endometrial cancers by immunohistochemical analysis. Nuclear immunoreactivity for FOXA1 was detected in 40 of 109 cases (37%), and was found to be negatively associated with lymph node status (P = 0.033). In ER-positive Ishikawa endometrial cancer cells, small interfering RNA-mediated downregulation of FOXA1 promoted cell proliferation and migration. Furthermore, exogenously introduced FOXA1 suppressed both proliferation and migration of Ishikawa cells. These results suggest that FOXA1 functions as a tumor suppressor through modulation of proliferation and migration of endometrial cancer cells.

Esophagus squamous cell carcinoma (ESCC) is one of the most deadly malignances because of its high frequency of metastasis. Given the associations of MUC1 with ESCC and tumor metastasis, we explored a potential role of MUC1 in ESCC metastasis. Among 40 ESCC and 20 paired normal tissue specimens examined, we found a significant increase of MUC1 expression in ESCC and more importantly, that expression of MUC1 and MMP13 are strongly correlated in patients who had lymph node metastasis. Studies with cell models indicated that overexpression of MUC1 upregulates the expression of MMP13, leading to increased cell migration. In support of a mode of transcriptional regulation, promoter analysis revealed that MUC1 stimulates MMP13 expression through the Runx-2-binding site. The link of MUC1 to cell motility was further confirmed by the finding that depletion of MUC1 resulted in reduced expression of MMP13 and cell migration, invasion and adhesion. Moreover, the loss of cell metastatic potential was rescued by overexpression of MMP13 completely. Collectively, our findings indicate that MUC1 contributes to ESCC metastasis by stimulating MMP13 expression, suggesting MUC1 as a novel diagnostic biomarker and therapeutic target in ESCC.

Signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in human cancer including lung cancer and has been implicated in transformation, tumorigenicity, and metastasis. One putative downstream gene regulated by Stat3 is MUC1 which also has important roles in tumorigenesis. We determined if Stat3 regulates MUC1 in lung cancer cell lines and what function MUC1 plays in lung cancer cell biology. We examined MUC1 expression in non-small cell lung cancer (NSCLC) cell lines and found high levels of MUC1 protein expression associated with higher levels of tyrosine phosphorylated STAT3. STAT3 knockdown downregulated MUC1 expression whereas constitutive STAT3 expression increased MUC1 expression at mRNA and protein levels. MUC1 knockdown induced cellular apoptosis concomitant with reduced Bcl-XL and sensitized cells to cisplatin treatment. MUC1 knockdown inhibited tumor growth and metastasis in an orthotopic mouse model of lung cancer by activating apoptosis and inhibiting cell proliferation in vivo. These results demonstrate that constitutively activated STAT3 regulates expression of MUC1, which mediates lung cancer cell survival and metastasis in vitro and in vivo. MUC1 appears to be a cooperating oncoprotein with multiple oncogenic tyrosine kinase pathways and could be an effective target for the treatment of lung cancer.

MUC1 expression has been described as a predictor for tumor progression and worsening of prognosis in various human neoplasms. However, little is known about the role of MUC1 expression in pulmonary metastatic tumors. The aim of this study is to examine the clinicopathological significance of MUC1 expression in pulmonary metastatic tumors (PMT). One hundred forty-seven patients with PMT who underwent (18)F-FDG PET before metastasectomy were included in this study. tumor sections were stained by immunohistochemistry for MUC1, glucose transporter 1 (Glut1), hypoxia-inducible-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF). (18)F-FDG uptake and the expression of these biomarkers were correlated in primary lung cancer. MUC1 expression pattern was classified into high-grade polarized expression (HP), low-grade polarized expression (LP), or depolarized expression (DP) group. Of 147 patients, HP, LP and DP group were 9 (6%), 114 (78%) and 24 (16%), respectively. The expression of Glut1, HIF-1alphaand VEGF, and (18)F-FDG uptake were significantly higher in DP group than HP or LP groups. MUC1 expression with HP and DP pattern was significantly higher in primary lung cancer than in PMT, whereas, MUC1 expression with LP pattern yielded a significantly high positive rate in PMT. LP group was recognized in the majority of patients with pulmonary metastatic adenocarcinoma, especially colon cancer, whereas, HP group was significantly low in pulmonary metastatic adenocarcinoma as compared with primary adenocarcinoma. Polarized MUC1 has a different expression pattern between primary and metastatic tumors with adenocarcinoma, and depolarized MUC1 is closely associated with glucose metabolism and hypoxia.

The MUC1 mucin is a large membrane-tethered glycoprotein that shows differential expression in many adenocarcinomas, where it contributes to their invasive and metastatic properties. We previously identified DNase I hypersensitive sites at -750 and -250 bp in the human MUC1 gene promoter and showed concordance between the -250 site and MUC1 mRNA levels in vivo. Transient expression assays using promoter constructs, in which the core DHS was deleted, to drive reporter gene expression revealed in vivo evidence for their activity. DNase I footprinting using nuclear extracts from HPAF human pancreatic carcinoma cells and MCF7 breast carcinoma cells identified three protein-binding elements in these regions (-250FP1, FP2 and -750FP). Electrophoretic mobility shift assays detected several complexes between HPAF nuclear proteins and labeled FP DNA probes. Southwestern blots and UV cross-linking experiments identified myeloid zinc finger-1 (MZF-1) as a candidate transcription factor among proteins binding to the -250FP1 and FP2 sequences. Another candidate that was identified by screening an HPAF cDNA expression library with the -250FP1 probe is DNA binding protein A (DbpA). Exogenous DbpA expression in COS-7 cells was accompanied by upregulation of MUC1 promoter activity via the -250 DHS, suggesting that DbpA binding to the -250 DHS can influence human MUC1 gene expression.

MUC1 is a highly glycosylated, type I transmembrane protein expressed by normal ductal epithelial cells of the pancreas, breast, lung, and gastrointestinal tract, and overexpressed in many cases of adenocarcinoma. We down-regulated MUC1 expression by RNA interference and investigated the effects on malignant and metastatic potential of a human pancreatic cancer cell line, S2-013. MUC1-suppressed clones, S2-013.MTII.C1 and S2-013.MTII.C2, were established by targeting a sequence 3,151 bp from the initiation codon and characterized in vitro for proliferation, invasion, and adhesion. We evaluated the effects of MUC1 suppression in vivo on tumor growth and metastatic properties following implantation into the cecum or pancreas of athymic mice. MUC1-suppressed clones showed significantly decreased proliferation in vitro and in vivo. Global gene expression was evaluated by oligonucleotide microarray analysis. Surprisingly, genes predicted to increase doubling times (cyclin B1 and cyclin D3) were overexpressed in MUC1-suppressed clones. There were alterations in expression of several genes that may affect the malignant properties of pancreatic cancer. Adhesion of MUC1-suppressed cells in vitro to type IV collagen and fibronectin was slightly increased, and adhesion was slightly decreased to type I collagen and laminin. Results of implantation to cecum and pancreas showed significant reduction of metastasis to lymph nodes, lung, or peritoneal sites compared with S2-013.gfp-neo control cells. These results support the hypothesis that MUC1 contributes significantly to growth and metastasis, and that down-regulation of MUC1 protein expression decreases the metastatic potential of pancreatic adenocarcinoma.

Adhesion of circulating tumor cells to the blood vessel endothelium is a critical step in cancer metastasis. We show in this study that galectin-3, the concentration of which is greatly increased in the circulation of cancer patients, increases cancer cell adhesion to macrovascular and microvascular endothelial cells under static and flow conditions, increases transendothelial invasion, and decreases the latency of experimental metastasis in athymic mice. These effects of galectin-3 are shown to be a consequence of its interaction with cancer-associated MUC1, which breaks the "protective shield" of the cell-surface MUC1 by causing MUC1 polarization, leading to exposure of smaller cell-surface adhesion molecules/ligands including CD44 and ligand(s) for E-selectin. Thus, the interaction in the bloodstream of cancer patients between circulating galectin-3 and cancer cells expressing MUC1 bearing the galectin-3 ligand TF (Galbeta1,3GalNAc-) promotes metastasis. This provides insight into the molecular regulation of metastasis and has important implications for the development of novel therapeutic strategies for prevention of metastasis.

Receptor tyrosine kinases and integrins play an essential role in tumor cell invasion and metastasis. We previously showed that EGF and other growth factors induce human carcinoma cell invasion and metastasis mediated by integrin alphavbeta5 that is prevented by Src blockade. MUC1, a transmembrane glycoprotein, is expressed in most epithelial tumors as a heterodimer consisting of an extracellular and a transmembrane subunit. The MUC1 cytoplasmic domain of the transmembrane subunit (MUC1.CD) translocates to the nucleus where it promotes the transcription of a metastatic gene signature associated with epithelial to mesenchymal transition. Here, we demonstrate a requirement for MUC1 in carcinoma cell metastasis dependent on EGFR and Src without affecting primary tumor growth. EGF stimulates Src-dependent MUC1 cleavage and nuclear localization leading to the expression of genes linked to metastasis. Moreover, expression of MUC1.CD results in its nuclear localization and is sufficient for transcription of the metastatic gene signature and tumor cell metastasis. These results demonstrate that EGFR and Src activity contribute to carcinoma cell invasion and metastasis mediated by integrin alphavbeta5 in part by promoting proteolytic cleavage of MUC1 and highlight the ability of MUC1.CD to promote metastasis in a context-dependent manner. Our findings may have implications for the use and future design of targeted therapies in cancers known to express EGFR, Src, or MUC1.

OBJECTIVE: The aim of our study was to determine the diagnostic value of MUC1 and MUC4 for distinguishing between metastatic adenocarcinoma cells (MAC) and reactive mesothelial cells (RMC) in effusion fluids. STUDY DESIGN: A total of 237 cell block specimens from pleural and peritoneal effusions, including 196 malignant effusions with MAC and 41 benign effusions with RMC, were stained with antibodies against MUC1 and MUC4. Membranous staining with or without cytoplasmic staining was considered to be positive. RESULTS: MUC1 immunoreactivity was observed in 194 (99.0%) of 196 cases of MAC and in 20 (48.8%) of 41 cases of RMC. MUC4 immunoreactivity was observed in 174 (88.8%) of 196 cases of MAC and in 4 (9.8%) of 41 cases of RMC. For distinguishing MAC from RMC, the MUC1 reactivity was found to be 99.0% sensitive and 51.2% specific with a positive predictive value of 90.7% and a negative predictive value of 91.3%. The sensitivity of MUC4 for MAC was 88.8%, the specificity was 90.2%, the negative predictive value was 62.7%, and the positive predictive value was 97.8%. CONCLUSION: Our data suggest that MUC4 appears to be a sensitive and specific marker for differentiating between MAC and RMC.

MUC1 is a transmembrane glycoprotein that modulates transcription via its cytoplasmic domain. We evaluated the capacity of MUC1 to regulate the global transcription of microRNAs in pancreatic cancer cells expressing MUC1. Results indicated that MUC1 regulated expression of at least 103 microRNAs. We evaluated further regulation of the microRNA transcript cluster miR-200c/141, which was among the most highly regulated microRNAs. We found that MUC1 directly interacted with ZEB1, a known transcriptional repressor of the miR-200c/141 cluster, at the promoter of miR-200c/141, and further reduced transcript production. These data indicate that signaling through MUC1 influences cancer progression by regulating transcription of microRNAs that are associated with the process of metastasis.

MUC1 is a transmembrane glycoprotein that modulates transcription via its cytoplasmic domain. We evaluated the capacity of MUC1 to regulate the global transcription of microRNAs in pancreatic cancer cells expressing MUC1. Results indicated that MUC1 regulated expression of at least 103 microRNAs. We evaluated further regulation of the microRNA transcript cluster miR-200c/141, which was among the most highly regulated microRNAs. We found that MUC1 directly interacted with ZEB1, a known transcriptional repressor of the miR-200c/141 cluster, at the promoter of miR-200c/141, and further reduced transcript production. These data indicate that signaling through MUC1 influences cancer progression by regulating transcription of microRNAs that are associated with the process of metastasis.

Molecular changes are vital for the development of prognostic markers and therapeutic modalities of prostate cancer (CaP). There is growing interest in mucins as treatment targets in human malignancies, including CaP. The role of their expression in the progression of CaP is however unclear. We examined the expressions MUC1, MUC2, MUC4, MUC5AC and MUC6 in CaP tissues using tissue microarrays (TMAs) to look for tumor-associated antigens (TAAs) for targeted therapy. In this study, 120 paraffin-embedded specimens were selected from patients who underwent radical retro-pubic prostatectomy (RRP) or trans-urethral-resection of the prostate (TURP) for primary, untreated CaP and 10 matched lymph node metastases. A series of MUC monoclonal antibodies (mAbs) was used on TMAs by standard immunohistochemistry. Our results indicate that the over-expression of MUC1 was detected in 58% of primary CaP tissues and 90% of lymph node metastases but not in normal prostate or benign tissues, while the expression of MUC2, MUC4, MUC5AC and MUC6 was found to be negative in both normal and cancer tissues. Of the MUC1 positive tumors 86% were Gleason grade 7 or higher. Over-expression of MUC1 was found in late stage CaP while MUC2, 4, 5AC and 6 were negative in CaP. MUC1 is a TAA that is highly related to tumor progression in CaP patients. This antigen is ideal for targeted therapy to control micrometastases and hormone refractory disease but additional studies are necessary to assess its usefulness in patient biopsies and CaP bone metastases before clinical trial.