Tissue-type plasminogen activator (tPA) in breast cancer: relationship with clinicopathological parameters and prognostic significance.
ABSTRACT Tissue-type plasminogen activator (tPA) is a serine protease primarily involved in the intravascular dissolution of blood clots. High intratumoral tPA levels are associated with prognosis in several human tumors. In addition, tPA has been shown to be an estrogen-inducible protein in human breast cancer cell lines. The aim of the present study was to analyze the cytosolic tPA content in primary breast carcinomas and its potential clinical value.
tPA was measured by a solid-phase enzyme immunoassay in tumor cytosol samples obtained from 800 patients with breast cancer. The median follow-up period was of 49.2 months.
Cytosolic tPA levels ranged widely in breast carcinomas (median: 3.9; range: 0.1- 315.3 ng/mg protein). tPA levels were significantly lower in large tumors, as well as in those showing poor differentiation, estrogen (ER) or PgR-negativity, aneuploidy, or a high S-phase fraction. In addition, low tPA intratumoral levels were associated with a high probability of both shortened relapse-free and overall survival in all patients and in the subgroup with node-negative tumors. However, our results did not show any significant relationship between intratumoral tPA levels and prognosis in the different subgroups of patients, stratified according to the type of systemic adjuvant therapy received (chemotherapy, tamoxifen or chemotherapy plus sequential tamoxifen).
The results of the present investigation indicate that low intratumoral tPA levels are associated with aggressiveness and poor prognosis in breast cancer patients. However, the study suggests that tPA levels do not predict response to systemic adjuvant therapy.
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ABSTRACT: Recent studies on the pattern of gene expression in estrogen receptor positive and negative tumours have revealed profound differences according to receptor status. However, it remains unclear if these differences reflect phenotypic traits in addition to sensitivity to endocrine therapy. This paper describes the long-term pattern of disease recurrence among ca. 2,600 pre- and post-menopausal patients with primary breast cancer according to estrogen receptor status. The study was based on patients with an operable, invasive breast cancer entered in one of three controlled clinical trials conducted by the Stockholm Breast Cancer Group. We selected those 2,562 patients who had been randomly allocated between adjuvant tamoxifen and no adjuvant systemic therapy. These patients had a known estrogen receptor status. Tamoxifen reduced locoregional (8.8% vs. 12.4%, hazard ratio (HR), 0.66; 95% CI, 0.52-0.83; P = 0.001, distant recurrences (17.2% vs. 20.2%, HR, 0.81; CI, 0.68-0.97; P = 0.018, as well as breast cancer death (18.7% vs. 23.7%, HR, 0.78; CI, 0.67-0.92; P = 0.002). Among patients not allocated to tamoxifen there was no significant differences in term of neither locoregional (12.4% vs. 12.4%, HR, 1; CI, 0.72-1.41; P = 0.98), nor distant metastases (18.5% vs. 20.7%, HR, 1.11;CI, 0.85-1.45; P = 0.46) according to ER status. The pattern of metastases was not different in ER positive comparison with ER negative. The results showed that the mentioned substantial differences in terms of gene expression appeared mainly to be related to endocrine sensitivity and not to metastatic potential. However, a slight advantage during the first five years for the ER positive versus ER negative patients in terms of cumulative incidence of events, suggested that ER negativity in some cases is correlated with an increased tumour growth rate.Breast Cancer Research and Treatment 02/2008; 107(1):71-8. · 4.47 Impact Factor
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ABSTRACT: Hyaluronic acid (HA), a high-molecular weight glycosaminoglycan, has been considered to be involved in the growth and progression of malignant tumors in several experimental studies. The objective of this work was to evaluate the cytosolic HA content in breast cancer, its possible relationship with clinicopathological tumor parameters and steroid receptor status, as well as its potential prognostic significance. Cytosolic HA levels were examined by means of immunoradiometric techniques in 850 patients with invasive breast cancer. The mean follow-up period for these patients was 55.1 months. Cytosolic HA levels ranged widely in tumors (4-59767 ng/mg protein; median: 4960). Statistical analysis showed that HA levels were significantly higher in younger patients (p=0.0001), as well as in premenopausal than in postmenopausal patients (p=0.001). HA levels were also significantly higher in ductal or lobular histological type than in other histological types (coloid, medullar or papillar types) (p=0.0001). Likewise, HA correlated significantly and positively with tumoral levels of PgR (r sub S: 0.11; p=0.001) in the all group of patients. In the subgroup of patients with ductal invasive type, HA levels were also significantly higher in well differentiated tumors and in diploid tumors. In addition, in this latter group of patients, HA levels in tumors correlated also positively and significantly with the either estrogen-inducible proteins: PgR (r sub S: 0.11; p=0.001), pS2 (r sub S: 0.117; p=0.008) and tPA (r sub S: 0.314; p=0.0001). On the other hand, significant association between HA intratumoral levels and relapse-free survival and overall survival in the overall group of patients was not found. However, high HA intratumoral levels were significantly associated with longer relapse-free survival in the subgroup of patients with ductal histological type tumors (p=0.01), as well as in those patients without any type of systemic adjuvant treatment (p=0.01). Our results suggest that high intratumoral levels of HA may be associated with tumors of favorable evolution in certain subgroups of patients with breast cancer. Thus, HA may provide additional prognostic information to that given by other biochemical markers currently used in breast cancer.Breast Cancer Research and Treatment 07/2006; 97(3):329-37. · 4.47 Impact Factor
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ABSTRACT: Glucocorticoid receptor (GR) activation can inhibit breast epithelial and cancer cells from undergoing programmed cell death in response to diverse apoptotic stimuli. Understanding the mechanisms underlying inappropriate cell survival mechanisms is important for treating breast cancer because if we can reverse these mechanisms, therapies designed to kill tumor cells are likely to be more effective. Recently, genome-wide DNA microarrays have provided a glimpse into the signals and interactions within regulatory pathways of the cell. These arrays enable simultaneous measurement of mRNA abundance of most, if not all, identified genes in a genome under different physiological conditions. Currently, two types of microarray experiments are frequently performed in laboratories. The first is a single time point microarray experiment, and the second is a time course microarray experiment. Single time point microarray experiments are effective in identifying genes regulated by a given treatment, e.g., direct target genes of a hormone treatment. However, because molecular pathways are dynamic processes that take place over time, single time point microarray experiments may not allow us to identify dynamic molecular pathways. This problem can be approached by performing a time course microarray experiment, which measures gene expression changes at various time points following a given treatment. In this chapter, we first describe how to identify target genes of a given treatment using a single time point microarray data analysis. We then present three alternate bioinformatics approaches to uncover molecular mechanisms from time course microarray data. Finally, we present a novel bioinformatics approach for analyzing time course microarray data in order to identify novel GR-mediated breast cancer cell survival pathways.12/2007: pages 165-183;