Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molybdate-stabilized androgen receptors have been quantitated in cytosols derived from 1026 malignant breast tumors including all new cases of primary breast cancer reported in the western region of Norway during the 3-year period 1985-1987. A simple single point saturation assay using the synthetic labeled ligand methyltrienolone was evaluated for this purpose. This approach also allowed the simultaneous determination of estrogen and progesterone receptor from the same cytosol preparation. The cytosol content of albumin was also recorded in order to control for dilution by extracellular proteins. Androgen receptor was the sex hormone receptor most frequently found both in primary and secondary breast cancer. In primary tumors 84.9% (723 of 852) showed a cytosol concentration higher than 10 fmol/mg protein compared to 71.2 and 67.1% for estrogen and progesterone receptors, respectively. This incidence is about 2 times higher than previously reported for androgen receptors in the literature and may be due to the stabilizing effects of molybdate and a serine protease inhibitor on the recovery of active binding sites in cytosol. Cytosol concentration of androgen receptor is generally lower than that of the other sex hormone receptors; the average level was 65.5 fmol/mg cytosol protein compared to 86.8 and 84.7 for estrogen and progesterone receptors, respectively. Both incidence and cytosol concentrations were lower for all sex hormone receptors in soft tissue metastasis than in the primary tumor. This decrease is not likely to be due to differences in tumor cellularity since metastatic tumors appear to be more cellular as judged from a lower cytosol content of extracellular proteins (albumin). No significant differences were observed in any parameter investigated between different metastatic sites (skin, lymph nodes). Androgen receptor levels were strongly correlated to estrogen and progesterone receptor concentration in both primary and secondary cancers. Cytosol androgen receptor concentration increases with age. This increase is more significant in metastatic than in primary tumors. Evidently, tumor cellularity is a confounding factor in primary tumors since tumor cytosols from younger patients showed a higher content of extracellular proteins. Receptor levels in lymph node metastasis did not exhibit age dependence. This may suggest that locally produced factors rather than circulating levels of sex steroids modulate tumor receptor expression. In metastatic tissues androgen receptors are present with twice the frequency of progesterone receptors and one in four of these tumors express androgen receptor as their sole sex hormone receptor. This supports the view that some of the beneficial effects of high dose progestin treatment of advanced breast cancer are mediated through the androgen receptor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Improved measurement of androgen receptors in human breast cancer. 258 56

Tumor invasion and metastasis are processes poorly understood at the molecular level. Maspin is a serine protease inhibitor (serpin) with tumor-suppressing function in the mammary gland. Maspin gene expression is decreased with malignancy and is lost in metastatic cells. We show in this report that differential expression of maspin in normal and carcinoma-derived mammary epithelial cells is regulated at the transcriptional level. We have identified the Ets and Ap1 sites in the maspin promoter that are active in regulating maspin expression in normal mammary epithelial cells but inactive in tumor cells. The Ets site alone is sufficient to activate transcription in a heterologous promoter, whereas the Ap1 site cooperates with Ets in activation. The enhancing function by Ets and Ap1 elements is decreased in primary tumor cells (21NT) and is abolished in invasive tumor cells (MDA-231). Thus, loss of maspin expression during tumor progression results at least in part from the absence of transactivation through the Ets and Ap1 sites.
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PMID:Transactivation through Ets and Ap1 transcription sites determines the expression of the tumor-suppressing gene maspin. 904 Sep 39

Maspin is a unique serine protease inhibitor of which the down-regulation is associated with the development of breast cancers. In vitro, recombinant maspin inhibits tumor cell migration and invasion. Overexpression of maspin in transgenic mice is protective against tumor progression. Additionally, maspin acts as an angiogenesis inhibitor in rat cornea model and in a xenograft tumor model. To additionally prove that maspin is directly involved in the suppression of tumor growth and metastasis, we tested maspin in a new syngeneic mammary tumor model, TM40D. This model involves the implantation of TM40D mammary tumor cells orthotopically to the mammary gland; tumors grew within the gland and then become invasive and metastatic to other organs. Here we demonstrate that TM40D cells in implanted mammary glands are highly invasive. Overall, a 75% rate of invasion and metastasis was observed in this model. However, both primary tumor growth and metastasis were significantly blocked in TM40D cells that overexpress maspin as a consequence of plasmid or retrovirus infection. Maspin-transfected tumors tended to have tumor encapsulation and less necrosis, which were associated with better prognosis and lower invasiveness. Thus, maspin can block primary tumor growth as well as invasion and metastasis. These data support the concept that maspin has a strong protective role against tumor progression.
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PMID:Blocking tumor growth, invasion, and metastasis by maspin in a syngeneic breast cancer model. 1155 74

Urokinase-type plasminogen activator (uPA) and plasmin have long been implicated in cancer progression. However, the precise contributions of the uPA/plasmin system to specific steps involved in cancer cell dissemination have not been fully established. Herein, we have used a highly disseminating variant of the human PC-3 prostate carcinoma cell line, PC-hi/diss, as a prototype of aggressive carcinomas to investigate the mechanisms whereby pro-uPA activation and uPA-generated plasmin functionally contribute to specific stages of metastasis. The PC-hi/diss cells secrete and activate significant amounts of pro-uPA, leading to efficient generation of plasmin in solution and at the cell surface. In a mouse orthotopic xenograft model, treatment with the specific pro-uPA activation-blocking antibody mAb-112 significantly inhibited local invasion and distant metastasis of the PC-hi/diss cells. To mechanistically examine the uPA/plasmin-mediated aspects of tumor cell dissemination, the anti-pro-uPA mAb-112 and the potent serine protease inhibitor, aprotinin, were used in parallel in a number of in vivo assays modeling various rate-limiting steps in early metastatic spread. Our findings demonstrate that, by generating plasmin, activated tumor-derived uPA facilitates early stages of PC-hi/diss dissemination, specifically the escape from the primary tumor and tumor cell intravasation. Moreover, through a series of in vitro and in vivo analyses, we suggest that PC-hi/diss-invasive escape and dissemination may be enhanced by cleavage of stromal fibronectin by uPA-generated plasmin. Together, our findings point to inhibition of pro-uPA activation at the apex of the uPA/plasmin cascade as a therapy-valid approach to control onset of tumor escape and ensuing metastatic spread.
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PMID:Activation of pro-uPA is critical for initial escape from the primary tumor and hematogenous dissemination of human carcinoma cells. 2196 14

High tumor kallikrein-related-peptidase 4 (KLK4) levels are associated with a poor outcome for women with serous epithelial ovarian cancer (EOC), for which peritoneal dissemination and chemoresistance are key events. To determine the role of KLK4 in these events, we examined KLK4-transfected SKOV-3 and endogenous KLK4 expressing OVCA432 cells in 3-dimensional (3D) suspension culture to mimic the ascites microenvironment. KLK4-SKOV-3 cells formed multicellular aggregates (MCAs) as seen in ascites, as did SKOV-3 cells treated with active KLK4. MCA formation was reduced by treatment with a KLK4 blocking antibody or the selective active site KLK4 sunflower trypsin inhibitor (SFTI-FCQR). KLK4-MCAs formed larger cancer cell foci in mesothelial cell monolayers than those formed by vector and native SKOV-3 cells, suggesting KLK4-MCAs are highly invasive in the peritoneal microenvironment. A high level of KLK4 is expressed by ascitic EOC cells compared to matched primary tumor cells, further supporting its role in the ascitic microenvironment. Interestingly, KLK4 transfected SKOV-3 cells expressed high levels of the KLK4 substrate, urokinase plasminogen activator (uPA), particularly in 3D-suspension, and high levels of both KLK4 and uPA were observed in patient cells taken from ascites. Importantly, the KLK4-MCAs were paclitaxel resistant which was reversed by SFTI-FCQR and to a lesser degree by the general serine protease inhibitor, Aprotinin, suggesting that in addition to uPA, other as yet unidentified substrates of KLK4 must be involved. Nonetheless, these data suggest that KLK4 inhibition, in conjunction with paclitaxel, may improve the outcome for women with serous epithelial ovarian cancer and high KLK4 levels in their tumors.
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PMID:Paclitaxel resistance and multicellular spheroid formation are induced by kallikrein-related peptidase 4 in serous ovarian cancer cells in an ascites mimicking microenvironment. 2345 Nov 43