Tissue-type plasminogen activator as marker of functional steroid receptors in human breast cancer

Rella, C.; Coviello, M.; Quaranta, Michele; Paradiso, Angelo

doi:10.1016/0049-3848(93)90046-q

Cited by 26 publications

(11 citation statements)

References 11 publications

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“…The median follow-up period, however, was considerably shorter (26 months). In agreement with other investigations, the cytosolic levels of tPA were positively related to steroid hormone receptor (ER and/or PgR) status (Duffy et al, 1986;Needham et al, 1988;Schmitt et al, 1990;Jänicke et al, 1991;Rella et al, 1993). In this respect, the observed correlation of high tPA antigen levels with good prognosis may be related to the fact that tPA is an oestrogen-inducible enzyme (Butler et al, 1983;Mira-YLopez and Ossowski, 1987), the presence of ER itself generally being associated with good prognosis in breast carcinomas (Table 2).…”

Section: Discussionsupporting

confidence: 78%

“…In this respect, the observed correlation of high tPA antigen levels with good prognosis may be related to the fact that tPA is an oestrogen-inducible enzyme (Butler et al, 1983;Mira-YLopez and Ossowski, 1987), the presence of ER itself generally being associated with good prognosis in breast carcinomas (Table 2). Therefore, the presence of tPA may be directly representative of a functional, biologically active ER system, important for planning endocrine therapy, as has been suggested by Rella et al (1993). The positive clinical impact of tPA on survival is also expressed by the combined prognostic value of tPA and PAI-1 measured in cytosols but mainly in pellet extracts (Figure 2), exemplifying that tPA abolishes the unfavourable effect of PAI-1 on prognosis.…”

Section: Discussionmentioning

confidence: 86%

“…Both uPA and PAI-1 are established prognostic factors in several types of cancer, a high tissue level of both components generally being associated with tumour progression and with poor disease-free and/or overall survival (reviewed by Duffy, 1996;Schmitt et al, 1997). Furthermore, several investigators have reported on the potential diagnostic and prognostic relevance of tPA analysed either in plasma or in tumour tissues from patients, including those afflicted with breast or colon cancer (Layer et al, 1987;De Bruin et al, 1988;Duffy et al, 1988;Needham et al, 1988;Grøndahl-Hansen et al, 1990;Jänicke et al, 1990Jänicke et al, , 1991Rella, et al, 1993;Yamashita et al, 1993Yamashita et al, , 1995Duggan et al, 1997). In addition, some studies even have examined the presence of complexes between tPA and PAI-1 in plasma from healthy individuals and patients with various diseases (Niwano et al, 1992;Hansson et al, 1994;Maser et al, 1997).…”

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confidence: 99%

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Prognostic value of tissue-type plasminogen activator (tPA) and its complex with the type-1 inhibitor (PAI-1) in breast cancer

et al. 1999

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SummaryThe prognostic value of tissue-type plasminogen activator (tPA) measured in samples derived from 865 patients with primary breast cancer using a recently developed enzyme-linked immunosorbent assay (ELISA) was evaluated. Since the assay could easily be adapted to the assessment of the complex of tPA with its type-1 inhibitor (PAI-1), it was investigated whether the tPA:PAI-1 complex also provides prognostic information. To this end, cytosolic extracts and corresponding detergent extracts of 100 000 g pellets obtained after ultracentrifugation when preparing the cytosolic fractions for routine steroid hormone receptor determination were assayed. Statistically significant correlations were found between the cytosolic levels and those determined in the pellet extracts (Spearman correlation coefficient r s = 0.75, P < 0.001 for tPA and r = 0.50, P < 0.001 for tPA:PAI-1 complex). In both Cox univariate and multivariate analysis elevated levels of (total) tPA determined in the pellet extracts, but not in cytosols, were associated with prolonged relapse-free (RFS) and overall survival (OS). In contrast, high levels of the tPA:PAI-1 complex measured in cytosols, but not in the pellet extracts, were associated with a poor RFS and OS. The prognostic information provided by the cytosolic tPA:PAI-1 complex was comparable to that provided by cytosolic (total) PAI-1. Furthermore, the estimated levels of free, uncomplexed tPA and PAI-1, in cytosols and in pellet extracts, were related to patient prognosis in a similar way as the (total) levels of tPA and PAI-1 respectively. Determination of specific forms of components of the plasminogen activation system, i.e. tPA:PAI-1 complex and free, uncomplexed tPA and/or PAI-1, may be considered a useful adjunct to the analyses of the separate components (tPA and/or PAI-1) and provide valuable additional prognostic information with respect to survival of breast cancer patients.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

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Prognostic value of tissue-type plasminogen activator (tPA) and its complex with the type-1 inhibitor (PAI-1) in breast cancer

et al. 1999

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“…Other androgen-responsive genes are known to be expressed by the same epithelial cells within proximal tubules, such as the kidney androgen-regulated protein (37), ␤-glucuronidase, ornithinedecarboxylase (38,39), and P450 cytochromes (40,41). Testosterone is considered to control the expression of the ␤-glucuronidase and ornithine-decarboxylase genes at a posttranscriptional level, whereas it increases the transcription rates of the kidney androgen-regulated protein and P450 cytochrome genes.…”

Section: Discussionmentioning

confidence: 99%

The kidney is a major site of alpha(2)-antiplasmin production.

Menoud¹,

Sappino²,

Boudal-Khoshbeen³

et al. 1996

J. Clin. Invest.

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The serpin ␣ 2 -antiplasmin ( ␣ 2 -AP) is the major circulating inhibitor of plasmin; it plays a determining role in the regulation of intravascular fibrinolysis. In addition to blood plasma, plasmin formation occurs in various organs where it is thought to fulfill a spectrum of functions not restricted to clot lysis. ␣ 2 -AP is synthesized by hepatocytes, but other possible sites of production have not been investigated. To explore the potential extravascular contribution of ␣ 2 -AP in the regulation of proteolysis, we have isolated the murine ␣ 2 -AP cDNA and determined its mRNA distribution in adult tissues.In

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“…The level of t-PA expression in breast carcinoma cells correlates with the endogenous level of progesterone receptor (8), and progesterone induces t-PA-related antigen secretion in primary human endometrial cells (9). Vitamin A, retinoic acid (RA), and some of its (synthetic) analogues induce t-PA-related antigen secretion by human umbilical vein endothelial cells in vitro (10 -12) and in the plasma as well as in specific tissues of vitamin A-deficient rats in vivo (11,13,14), suggesting that circulating RA might regulate t-PA expression in the vessel wall.…”

mentioning

confidence: 99%

Identification of a Multihormone Responsive Enhancer Far Upstream from the Human Tissue-type Plasminogen Activator Gene

Bulens

Merchiers²,

Ibañez–Tallon³

et al. 1997

Journal of Biological Chemistry

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A 2.4-kilobase (kb) DNA fragment, located 7.1 kb upstream from the human tissue-type plasminogen activator (t-PA) gene (t-PA2.4), acts as an enhancer which is activated by glucocorticoids, progesterone, androgens, and mineralocorticoids. Transient expression of t-PAchloramphenicol acetyltransferase reporter constructs in HT1080 human fibrosarcoma cells identified a glucocorticoid responsive unit with four functional binding sites for the glucocorticoid receptor, located between bp ؊7,501 and ؊7,974. The region from bp ؊7,145 to ؊9,578 (t-PA2.4) was found to confer a cooperative induction by dexamethasone and all-trans-retinoic acid (RA) to its homologous and a heterologous promoter, irrespective of its orientation. The minimal enhancer, defined by progressive deletion analysis, comprised the region from ؊7.1 to ؊8.0 kb (t-PA0.9) and encompassed the glucocorticoid responsive unit and the previously identified RA-responsive element located at ؊7. Vascular patency is the result of a dynamic equilibrium between blood coagulation and fibrinolysis. Injury of the vessel wall can initiate the blood clotting cascade resulting in the formation of a hemostatic clot. To counterbalance fibrin deposition, blood contains the fibrinolytic system, one main function of which is to dissolve blood clots in the circulation. It is composed of the inactive precursor plasminogen, which can be converted into the proteolytic enzyme plasmin by the plasminogen activators (PAs) 1 tissue-type and urokinase-type PA (t-PA and u-PA, respectively) leading to the degradation of fibrin. Fibrinolytic activity can be inhibited both at the level of the PAs and plasmin by PA inhibitors (PAI-1 and -2) and ␣ 2 -antiplasmin, respectively (for a review, see ref. 1). Phenotypic analysis of mice deficient for either t-PA, u-PA, or both suggested that t-PA and u-PA were complementary, not only in the prevention of uncontrolled fibrin deposition in vivo but also in distinct processes which require local extracellular proteolytic activity, such as wound healing and gonadotropin-induced ovulation, as reviewed elsewhere (2).Dexamethasone, a synthetic glucocorticoid, and androgens increase t-PA synthesis in vitro (3-5) and in vivo (6, 7). The level of t-PA expression in breast carcinoma cells correlates with the endogenous level of progesterone receptor (8), and progesterone induces t-PA-related antigen secretion in primary human endometrial cells (9). Vitamin A, retinoic acid (RA), and some of its (synthetic) analogues induce t-PA-related antigen secretion by human umbilical vein endothelial cells in vitro (10 -12) and in the plasma as well as in specific tissues of vitamin A-deficient rats in vivo (11,13,14), suggesting that circulating RA might regulate t-PA expression in the vessel wall. The induction of t-PA expression by glucocorticoids and RA can be reproduced in HT1080 human fibrosarcoma cells, and interestingly, both agents induce t-PA mRNA steady state levels and t-PA-related antigen secretion in a cooperative manner.2 Both steroid hormones and RA are t...

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Tissue-type plasminogen activator as marker of functional steroid receptors in human breast cancer

Cited by 26 publications

References 11 publications

Prognostic value of tissue-type plasminogen activator (tPA) and its complex with the type-1 inhibitor (PAI-1) in breast cancer

Prognostic value of tissue-type plasminogen activator (tPA) and its complex with the type-1 inhibitor (PAI-1) in breast cancer

The kidney is a major site of alpha(2)-antiplasmin production.

Identification of a Multihormone Responsive Enhancer Far Upstream from the Human Tissue-type Plasminogen Activator Gene

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