Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the effect of a progestin (lynestrenol) on estrogen receptors (ER) and cathepsin D (cath-D) levels immunochemically in successive fine needle aspirates of benign breast disease. Fibrocystic disease was the main pathology (43 out of 47 patients). Thirty-one patients were treated with 10 mg of lynestrenol daily from the fifth to the twenty-fifth day of the menstrual cycle for 1 to 3 months. Sixteen untreated patients were used as controls. Lynestrenol significantly decreased the percentage of ER stained cells. This is in agreement with the antiestrogenic effect of progestin and, for the first time, indicates that in vivo progestin may decrease the stimulatory effect of estrogens on mammary cells by decreasing their estrogen receptor content. No effect of progestin on cath-D level was found throughout the whole population. However, this level varied more between aspirates of each patient in the treated group than in the control group, suggesting heterogeneity in patient responses to progestin. Since cath-D may have a role in carcinogenesis, clinical follow-up of these patients and more detailed studies are required to determine whether this progestin-challenge test has any value for detecting high risk mastopathies and for predicting effectiveness of treatment.
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PMID:Progestin treatment depresses estrogen receptor but not cathepsin D levels in needle aspirates of benign breast disease. 175 73

Fibronectin is one of the major adhesive glycoproteins and bears interaction sites for both cell receptors and the extracellular matrix. Disappearance of fibronectin is the first step of cellular transformation in carcinogenesis. This phenomenon has been ascribed to increased proteolysis of fibronectin or of its cellular receptor. Results obtained during previous studies by the authors have shown that the fibronectin molecule has latent proteolytic activities which become apparent only after the action of other external proteases. Two proteinases, FN-gelatinase and FN-laminase, were identified in cathepsin D fibronectin digest. The acute activity of these two proteases is responsible for degradation of the extracellular matrix. Furthermore, the sequences and functions of both enzymes share a number of features with retroviral proteases.
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PMID:[Proteolytic potential of fibronectin and degradation of extracellular matrix]. 229 Jul

Pro-cathepsin D is overexpressed in breast cancer cells compared to normal mammary epithelial cells. Moreover, its processing and maturation are altered resulting in increased secretion. In estrogen-responsive breast cancer cell lines such as MCF7 cells and ZR75-1 cells, the 2.2-kb cathepsin D mRNA is accumulated specifically by estrogens and growth factors. Estrogen regulation is mostly transcriptional, while growth factors stabilize the mRNA and act indirectly. In estrogen-receptor-negative cell lines, there is a constitutive high production of cathepsin D mRNA. Moreover in uterine cells, progesterone is the inducer rather than estrogen, indicating the complexity of regulation by steroids, depending on the tissue. The increased production of cathepsin D appears to be correlated with the aggressiveness of the tumour, as shown by retrospective clinical studies, suggesting a role in mammary carcinogenesis.
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PMID:Overexpression and hormonal regulation of pro-cathepsin D in mammary and endometrial cancer. 262 16

Human breast cancer is characterised by its high frequency of metastasis and its oestrogen responsiveness, allowing specific anti-oestrogen therapy. Oestrogens are promoting agents that stimulate early steps of mammary carcinogenesis. The availability of several oestrogen receptor (ER)-positive and ER-negative human breast cancer metastatic cell lines has allowed characterisation of several hormone-regulated genes, some of which are involved in growth and metastasis. Moreover, these models have allowed examination of the mechanisms by which hormone antagonists (anti-oestrogens and anti-progestins) act on their respective receptors to inhibit tumour growth. By contrast, no convenient in vitro models are available to investigate the mode of action of oestrogens and anti-oestrogens on non-malignant mammary cells. Among the oestrogen-regulated genes, some are also regulated by growth factors, such as the cathepsin D gene, whose overexpression in primary breast cancers has been associated with relapse and metastasis in several retrospective clinical studies. The mechanism and consequences of cathepsin D overexpression on metastasis are reviewed. From these studies on cell lines, new immunological and genetic probes have been raised that can be applied to breast cancer tissue to titrate in patients expression of different genes involved in the control of mammary tumour growth and invasion. These tissue markers should help to stratify primary breast cancers according to their ability to metastasise and respond to therapies and consequently to choose the best therapy. Over the next decade, these studies should lead to new therapeutical approaches of breast cancers which resist classical systemic therapies.
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PMID:Oestrogens, proteases and breast cancer. From cell lines to clinical applications. 783 23

Cathepsin D serum mass concentrations were determined by enzyme immunoassay in patients with hepatocellular carcinoma (n = 51) and/or liver cirrhosis (n = 92) or benign steatosis (n = 16) and correlated with some biochemical and clinical properties of these diseases. Increased cathepsin D serum mass concentrations (P < 0.001) were observed in all these groups of patients as compared to normal subjects (n = 98). However, patients with steatosis had serum mass concentrations of this enzyme significantly lower (mean 2-3 fold) than those measured in cancer patients (P < 0.05) or cirrhotic patients (P < 0.001). Interestingly, significantly higher cathepsin D serum mass concentrations (mean + 62%) (P < 0.006) were determined in the cirrhosis group as compared to cancer patients. No correlation between cathepsin D and a number of clinical and biochemical properties examined, namely, alpha-foetoprotein, number of neoplastic lesions and tumour size in cancer patients or, Child-Pugh grade of severity of cirrhosis and other enzymes of liver function tests in the cirrhotic group was found. The present data and those from other studies which indicate that cathepsin D may be involved in carcinogenesis suggest that this enzyme may be potentially useful as an additional biochemical marker to identify cirrhotic patients who may develop precancerous hepatic nodules.
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PMID:Cathepsin D serum mass concentrations in patients with hepatocellular carcinoma and/or liver cirrhosis. 886 4

In a large series of more than 100 cases of laryngeal carcinomas, the presence of steroid hormone receptors was demonstrated in the cytosol and in the nuclear fraction. Their presence was confirmed by the identification of estrogen receptor isophorms and by the detection of hormone-related proteins such as ER-D5. EGFr, and cathepsin D. These molecules were also variably expressed in normal, hyperplastic, and dysplastic epithelium. These data suggest a possible role of hormone receptors during laryngeal carcinogenesis. Finally, the presence of an Angiotensin II receptor was studied in neoplastic and preneoplastic laryngeal epithelium.
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PMID:Molecular biopathology of metaplastic, dysplastic, and neoplastic laryngeal epithelium. 919 78

We have proposed that an early step in estrogen carcinogenesis in the hamster kidney is tubular damage followed by reparative cell proliferation. This tubular injury is progressive and increases in severity with continued estrogen treatment; one pertinent feature is a marked rise in the number of both secondary and tertiary lysosomes. Data presented herein indicate that cathepsin D, an estrogen-responsive lysosomal proteolytic enzyme, is increased in the kidney following estrogen treatment in the hamster. Three isoforms of cathepsin D were detected in estrogen-treated kidneys, 52, 31, and 27 kDa, the major being 52 kDa. At 1 and 3 months of estrogen treatment, 52-kDa cathepsin D content increased 1.4- to 1.6-fold. These changes coincided with a rise in renal estrogen receptor levels during the same estrogen treatment periods. More pronounced rises in cathepsin D levels, 2.7- and 3.5-fold, were seen after 4 and 5 months of estrogen treatment, respectively. A concomitant, 3.0- to 4.0-fold rise in estrogen receptor content was also observed. At 5 months of estradiol or DES treatment, both 27- and 31-kDa isoforms were present in hamster kidneys, in addition to the 52-kDa form. Neither progesterone nor DHT treatment affected the untreated levels of cathepsin D. Interestingly, either concomitant tamoxifen or DHT and estrogen treatment prevented the rise in cathepsin D and estrogen receptor content observed after estrogen treatment alone. Primary estrogen-induced renal tumors and their metastases exhibited markedly elevated levels of all three isoforms of cathepsin D. Immunohistochemical analysis of cathepsin D in kidney sections confirmed the Western blot findings. These data suggest a novel role for estrogen-induced cathepsin D in the hamster kidney during tumorigenesis; that is, mediating renal tubular damage as a prelude to reparative cell proliferation, thus initiating a multi-step estrogen-driven process which leads to renal tumor formation.
Carcinogenesis 1997 Jul
PMID:Induction of cathepsin D protein during estrogen carcinogenesis: possible role in estrogen-mediated kidney tubular cell damage. 923 Feb 83

The insulin-like growth factors (IGF-I and -II) are structurally related peptides participating in the regulation of metabolism, growth and cellular differentiation. In the present study, the human hepatoma cell line PLC was studied for the expression of individual components of the IGF axis. Northern blot analysis using IGF-I and -II coding cDNAs failed to detect IGF-I- or -II-specific transcripts in total RNA from PLC cells. Biosynthesis of type I and II IGF receptors was demonstrated by northern blotting and binding studies as well as cross-linking of the respective radiolabeled ligand. Both IGF-I and -II stimulated [3H]-thymidine incorporation dose-dependently. The mitogenic activity of exogenously added IGFs was reduced by the presence of IGF-binding proteins of 24, 30, 34, 41 and 45 kDa in supernatants of PLC cells identified as IGFBP-4, -1, -2 and -3, respectively, by [125I]IGF-I ligand-, immuno- and northern blotting. Biosynthesis of IGFBP-3 was stimulated dose-dependently by IGF-I and -II, while IGFBP-1, -2 and -4 were not affected. The increase of IGFBP-3 in response to IGF-I and -II was due to a stimulation of IGFBP-3 specific mRNA as well as to an inhibition of IGFBP-3 endocytosis. Proteolytic activity for rhIGFBP-3 was detected in media from PLC cells at acidic pH that was inhibited by the aspartyl protease inhibitor pepstatin A as well as after immunodepletion of cathepsin D from media of PLC cells. Thus, a role of cathepsin D for the regulation of IGFBP-3 bioavailability via endocytosis in acidic prelysosomal compartments was suggested. The susceptibility of PLC for IGF-I and -II was restricted by their ability to increase the abundance of inhibitory IGFBPs and to decrease the level of IGF-I receptor expression. The present data point to the IGF axis as a complex regulatory system that self limits the mitogenic activity of exogenous IGFs.
Carcinogenesis 1998 Dec
PMID:Characterization of the insulin-like growth factor axis in a human hepatoma cell line (PLC). 988 66

The mammary gland seems to be the only organ that is not fully developed at birth. Estrogens stimulate breast tissue via estrogen receptors (ERs). In the mammary gland, ER-mediated mechanisms have been shown to regulate: various growth factors, such as TGF-alpha and TGF-beta; enzymes, such as cathepsin D and plasminogen-activator; proto-oncogenes, such as c-fos, c-myc and HER-2/neu; cyclines and other regulatory substances that provide signaling systems for cell division and differentiation; other steroid receptors and epidermal growth factor receptors. Estrogen target genes contain estrogen-responsive elements. In these genes, transcription will be activated through interaction with the estrogen/ER protein complex. Subsequent activation of proto-oncogenes provides an explanation for the stimulating effect of estrogens on the glandular breast. Progesterone may be the key in influencing the risk of breast cancer with the peak of mitotic activity in the breast during the luteal phase of the menstrual cycle. On the other hand, in human breast cancer cell lines, both proliferation and inhibition have been observed with various progestational agents. Relevant biological and clinical issues are pregnancy and exposure to exogenous hormones. The intense hormonal stimulation of pregnancy (both estrogen and progesterone) has no adverse impact on the course of breast cancer. Pregnancy, with its mammogenetic differentiation, results in the protection of this organ from carcinogenesis. Characterization of specific lobular morphology serves as an indicator of the level of differentiation achieved by the organ, and thus provides means to assess the risk of the gland undergoing neoplastic transformation when exposed to given agents. Sufficient evidence exists to indicate the possibility of a slightly increased risk of breast cancer after approximately one decade of postmenopausal estrogen use. A review of the epidemiologic studies of postmenopausal hormone replacement and the risk of breast cancer fails to provide definitive evidence. Recent information derives from observations of cellular proliferation, plasma and tissue estradiol and progesterone receptor levels, and the percentage of apoptotic epithelial cells in human breast tissue. Several studies suggest that short-term, continuous combined HRT does not increase breast cancer recurrence or mortality. The participation of sexual hormones in the mammogenetic process during pregnancy might serve as an intermediate end point in assessing the effectiveness of hormones as chemopreventive agents. Investigations based on history, and breast morphology, should enable us to select estrogens and progestogens for HRT, and adopt optimal therapeutic regimens.
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PMID:Potential benefits of estrogens and progestogens on breast cancer. 992 May 36

3,3',4,4'-Tetrachlorobiphenyl (tetraCB) binds to the aryl hydrocarbon receptor (AhR), and several reports have demonstrated that AhR agonists exhibit antiestrogenic and antitumorigenic activities in human breast cancer cells, the rodent uterus and breast. In contrast, a recent study showed that 3,3',4,4'-tetraCB bound the estrogen receptor (ER) and exhibited ER agonist activities, and we therefore have reinvestigated the estrogenic and antiestrogenic activities of 3,3',4,4'-tetraCB. Our results showed that 3,3',4,4'tetraCB and a structurally related analog, 3,3',4,4',5-pentaCB, did not bind the mouse uterine or human ER, did not induce proliferation of MCF-7 or T47D human breast cancer cells or induce reporter gene activity in cells transfected with E2-responsive constructs derived from the creatine kinase B (pCKB) or cathepsin D (pCD) gene promoters. Moreover, 3,3',4,4'-tetraCB and 3,3',4,4',5-pentaCB did not induce an increase in uterine wet weight, peroxidase activity or progesterone receptor binding in the 21-25-day-old female B6C3F1 mouse uterus. In contrast, both compounds inhibited 17beta-estradiol (E2)-induced cell proliferation and transactivation in MCF-7/T47D cells and uterine responses in B6C3F1 mice; surprisingly inhibition of E2-induced reporter gene activity was not observed in T47D cells transfected with pCKB, and this was observed as a cell-specific response with other AhR agonists. Additionally, 3,3',4,4'-tetraCB significantly inhibited mammary tumor growth in female Sprague-Dawley rats initiated with 7,12-dimethylbenzanthracene. Our results indicate that 3,3',4,4'-tetraCB does not exhibit ER agonist activity but exhibits a broad spectrum of antiestrogenic responses consistent with ligand-mediated AhR-ER crosstalk.
Carcinogenesis 1999 Jan
PMID:3,3'4,4'-Tetrachlorobiphenyl exhibits antiestrogenic and antitumorigenic activity in the rodent uterus and mammary cells and in human breast cancer cells. 993 58


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