Cathepsin-D in primary breast cancer: prognostic evaluation involving 2810 patients

Abstract

Cathepsin-D is a lysosomal aspartyl protease which is expressed in all tissues. In breast cancer, it was first identified as a 52-kDa oestrogen-regulated secretory glycoprotein with autocrine mitogenic activity (Westley and Rochefort, 1979, 1980;Vignon et al, 1986;Rochefort, 1994;Westley and May, 1996). In oestrogen receptor (ER)-positive breast cancer cells, its gene transcription is increased by oestrogen and growth factors, whereas in ER-negative breast cancer cells it is constitutively expressed by an unknown mechanism. Many biological roles have been attributed to cathepsin-D (reviewed by Westley and May, 1996), including, among others: degradation of the extracellular matrix (Briozzo et al, 1988), increasing cells' malignant phenotype and metastatic potential (Garcia et al, 1990), stimulation of (metastatic) cell proliferation by increasing the local bioavailability of growthstimulatory growth factors (Briozzo et al, 1991;Conover and De Leon, 1994), inactivation of a growth inhibitor (Liaudet et al, 1995), and prevention of apoptosis (Saftig et al, 1995).In patients with primary breast cancer, overexpression of cathepsin-D was found to be related to a poor prognosis (Thorpe et al, 1989;Spyratos et al, 1989), in analogy with observations made with the serine protease urokinase-type plasminogen activator (uPA), of which increased activity (Duffy et al, 1988) and antigen level (Jänicke et al, 1990) have been shown to be associated with a poor prognosis. The initial studies of Thorpe et al (1989) andSpyratos et al (1989), using quantitative immunoassays (enzyme-linked immunosorbent assay, immunoradiometric assay) to assess cytosolic cathepsin-D levels, have been confirmed by many others employing the same technique (reviewed by Rochefort, 1994;Westley and May, 1996). However, utilization of other methods to assess cathepsin-D status, i.e. Western blotting and immunohistochemistry, resulted in discrepant results (Henry et al, 1990;Tandon et al, 1990;Domagala et al, 1992, Isola et al, 1993Ravdin, 1993, Ravdin et al, 1994Westley and May, 1996). These conflicting results have been attributed to the use of different antibodies without standardized quantification (Cardiff, 1994; Rochefort, 1996, Westley andMay, 1996), a problem which is not encountered when quantitative immunoassays on cytosolic extracts are used (Benraad et al, 1992).Notwithstanding the drawbacks of immunohistochemistry and contrasting data (Cardiff, 1996;Emmert-Buck, 1996; Rochefort, 1996, Westley andMay, 1996), there is evidence that the expression of cathepsin-D by host stromal cells (Têtu et al, 1993;Joensuu et al, 1995;O'Donoghue et al, 1995;Nadji et al, 1996), or the cancer cells (Isola et al, 1993), is associated with prognosis. It has been suggested that measuring total cathepsin-D levels in tumour extracts (comprising tumour cells and host cells) has no practical value (Nadji et al, 1996). This firm conclusion drawn from data obtained from only 154 patients is surprising. In contrast to conflicting data obtained with immunohistochemistry,...

Mammographic compression: a force to be reckoned with

“…Prognostic value of cathepsin D in breast cancer Sir A recent publication in this journal demonstrated, that cathepsin D was an independent marker of poor prognosis in 2810 breast cancer patients (Foekens et al, 1999). A covering editorial rose questions on the still unexplained biological role of cathepsin D in breast cancer (Westley et al, 1999).…”

Prognostic value of cathepsin D in breast cancer

“…It was hoped that it would prove more reliable than existing markers such as the oestrogen receptor; however, the promise of cathepsin D as a marker of oestrogen responsiveness has not been fulfilled. Interest in this protease has continued as a result of reports that it is a marker of poor prognosis in node-negative breast cancer patients (Spyratos et al, 1989;Foekens et al, 1996). The value of identifying markers of poor prognosis in node-negative breast cancer is that we need to be able to identify those women in this good-prognosis group who are at significant risk of relapse and who would be likely to benefit from a more aggressive treatment regimen.…”

“…The paper in this edition by John Foekens's group at the Rotterdam Cancer Institute (Foekens et al, 1998) represents something of a landmark in the assessment of cathepsin D as a prognostic marker in breast cancer. It demonstrates unequivocally that cathepsin D is an independent marker of poor prognosis in all groups of breast cancer patients.…”

“…The major issue addressed by the paper of Foekens et al (1998) is one that has been facing breast cancer patients, the clinicians treating them and the pharmaceutical company involved in producing the cathepsin D assay for more than 10 years, i.e. the usefulness of cathepsin D as a prognostic marker to identify women with a high risk of relapse.…”

“…Evaluation of cathepsin D as a prognostic marker has been seriously hampered both by the numbers of patients included in the clinical studies (very few studies have involved more than 150 patients) and by the relatively short follow-up times (Westley and May, 1996). The study of Foekens et al (1998) is remarkable in that it involved the analysis of 2810 cytosolic extracts and the median follow-up time of patients still alive at the time of the analysis was 88 months. The majority of the data were analysed by separating cathepsin D levels into quartiles or by dichotomizing the data using a cut-off value close to that of the median.…”