Original Article
Cathepsin D and Prognosis in Breast Cancer
N Engl J Med 1990; 322:297-302February 1, 1990
- Abstract
- Abstract
We investigated the possibility that cathepsin D, an estrogen-induced lysosomal protease, might have value as a prognostic factor in breast cancer by studying frozen tissue specimens from 397 patients. We measured the 34-kd mature form of the enzyme by Western blot assay and densitometry. Among 199 patients with node-negative disease, but not among 198 with node-positive disease, high levels of cathepsin D proved to be a significant predictor of reduced disease-free survival (median follow-up, 64 months), either as a continuous variable (log cathepsin D; P = 0.018) or as a dichotomous variable with an optimized cutoff point (P = 0.0001). Results were similar for overall survival (P = 0.009 and 0.0001, respectively).
Relating the level of cathepsin D to other prognostic factors in the patients with node-negative disease, we found an association with aneuploidy but none with estrogen or progesterone receptors, tumor size, or the age of the patient. In multivariate analyses, a high level of cathepsin D was the most important independent factor in predicting shorter disease-free and overall survival in patients with node-negative disease. As compared with the risk in women with low levels of cathepsin D, the relative risk of tumor recurrence was 2.6 (95 percent confidence interval, 1.6 to 4.4) and the relative risk of death was 3.9 (95 percent confidence interval, 2.1 to 7.3) among those with high levels of cathepsin D. For disease-free survival, cathepsin D status was predictive of outcome primarily among those with aneuploid tumors; the actuarial five-year recurrence rates of aneuploid tumors were 60 percent among women with high levels of cathepsin D and 29 percent among those with low levels, as compared with 22 percent for all diploid tumors. We conclude that cathepsin D may be an independent predictor of early recurrence and death in node-negative breast cancer. (N Engl J Med 1990; 322: 297–302.)
Media in This Article
Figure 1
Semiquantitation of Cathepsin D in Tumor Specimens by Western Blot Analysis.Figure 2
Distribution of the Concentration of Cathepsin D in 199 Node-Negative and 198 Node-Positive Breast Tumors.Article Activity
- Article
THE identification of more accurate predictors of relapse or survival in patients with cancer of the breast might improve the selection of therapy and guide further investigation into basic biologic questions concerning such tumors.
In 1979, Westley and Rochefort first described a 52-kd glycoprotein whose secretion into culture medium by hormone-dependent human breast cancer cell lines was specifically increased by estrogens and inhibited by antiestrogens.1 It was also found to be produced constitutively in some hormone-independent breast cancer cell lines. After its purification, the 52-kd protein was identified as the precursor of cathepsin D lysosomal acidic protease.1
In normal cells, only a small amount of cathepsin D is secreted as a 52-kd precursor; the bulk of the newly synthesized protein is targeted to the lysosomes, where it is proteolytically processed to an intermediate 48-kd single-chain form of the enzyme and the mature, stable 34- and 14-kd two-chain form.2 In addition to its ubiquitous role in the lysosomes, two biologic activities of the secreted precursor have been demonstrated in vitro: it has mitogenic activity on estrogen-depleted MCF-7 cells, suggesting that it is an estrogen-regulated autocrine mitogen, and an acidic proteolytic activity on various substrates, including proteoglycans and basement membranes.1 Both the growth-promoting activity and extracellular proteolytic activity suggest that cathepsin D may have prognostic importance in breast cancer. Indeed, with the use of monoclonal antibodies, levels of cathepsin D were found to be elevated in both benign and malignant proliferative ductal mastopathy, whereas they were very low or negligible in normal resting mammary glands and in lobular hyperplasia.3 In breast cancer, cytosolic 52-kd cathepsin D levels have been correlated with the status of estrogen receptors but not with other known prognostic factors.4 An unpublished study discussed by Rochefort et al.5 suggested a potential prognostic value of cathepsin D.
To evaluate more fully the clinical importance of cathepsin D in breast cancer, we used a semi-quantitative Western blot procedure to measure the enzyme's mature form (the 34-kd heavy chain) in a cohort of 397 women with primary tumors, and correlated these findings with those on other established prognostic factors, tumor recurrence, and patient survival. We found that cathepsin D is a potentially important prognostic factor for early recurrence and death in node-negative breast cancer, independently of a number of other prognostic variables.
Methods
Patients
Tumor specimens from 397 patients with primary breast tumors (198 node positive and 199 node negative) were evaluated in this study. The specimens were drawn from a pool of frozen specimens originally submitted to our laboratory for estrogen-receptor analysis beginning more than 15 years ago by clinical collaborators nationwide. Patients were followed up for disease recurrence and survival status as described elsewhere.6 Median clinical follow-up was 56 months for patients with node-positive cancer and 64 months for those with node-negative cancer. A computerized data base containing continually updated clinical information on each patient, along with receptor status, nodal status, ploidy, the number of positive nodes, the size of the primary tumor, the age of the patient, and the stage of the disease at diagnosis, was available for statistical analyses. Selection for the study required only that this information be available and that sufficient tumor remain for the assay; it was otherwise random.
Collection and Storage of Breast-Tumor Specimens
Breast-tumor specimens were frozen in liquid nitrogen immediately after excision and stored at —70°C. Tissues were pulverized in the frozen state and kept at —70°C until required for assay. Samples were fixed with formalin, embedded in paraffin, stained with hematoxylin–eosin, and examined microscopically to confirm the presence of tumor cells. All 397 specimens analyzed for cathepsin D contained tumor cells.
MCF-7 Cells
MCF-7 human breast cancer cells were grown in minimal essential medium supplemented with 10 mM HEPES buffer, nonessential amino acids, 2 mmol of glutamine per liter, 25 μg of gentamycin per milliliter, 6 ng of bovine insulin per milliliter, and 5 percent calf serum. Sodium bicarbonate (0.2 percent) was added to adjust the final pH to approximately 7.2. Cells were allowed to grow at 37°C in an atmosphere containing 5 percent carbon dioxide. Confluent cells were harvested by a brief incubation with 1 mM EDTA in phosphate-buffered saline, washed twice with phosphate-buffered saline, and stored as cell pellets at —70°C until assayed.
Steroid-Receptor Assays
Estrogen receptors and progesterone receptors in the tumor specimens were assayed as detailed elsewhere.7 , 8 Tumor specimens were considered estrogen-receptor—positive if they contained at least 3 fmol of specific binding sites per milligram of cytosolic protein, and progesterone-receptor—positive if they contained at least 5 fmol per milligram of cytosolic protein.
Determination of Ploidy
The DNA content of the tumor cells was determined as described previously.9 The DNA content was described as diploid if after the addition of human peripheral-blood lymphocytes to the tumor sample, we observed a superimposition of the G0/G1 peaks. The DNA content was defined as aneuploid if discrete G0/G1 peaks could be confirmed after the addition of peripheral-blood lymphocytes. In addition, the aneuploid G0/G1 peak had to contain at least 10 percent of the 50,000 sample events collected and have a corresponding G2+M peak.
Measurement of Cathepsin D
Total proteins from tumor specimens or cell pellets were extracted as described elsewhere.10 Briefly, approximately 10 mg of tumor powder or cell pellet was treated with 150 μl of 5 percent sodium dodecyl sulfate and boiled for five minutes; the protein extract was then collected by centrifugation at 13,000Xg for two minutes. The insoluble pellet from the tumor powder was once again treated with 150 μl of 5 percent sodium dodecyl sulfate. The first and second supernatants were combined, and the protein concentration was determined by the bicinchoninic acid method.11
Under denaturing, reducing conditions, 200 μg of tumor proteins were resolved on 10 percent polyacrylamide gels.12 Three concentrations (200 μg, 100 μg, and 50 μg of protein, corresponding to 100, 50, and 25 arbitrary units of cathepsin D) of a constant sodium dodecyl sulfate extract of MCF-7 cells were included on each gel as an internal laboratory standard. Resolved proteins were transblotted to 0.45-μm nitrocellulose membranes (Schleicher and Schuell) at 200 mA for 16 hours at 4°C by the method of Towbin et al.13 After blocking with 5 percent condensed milk (Carnation) for one hour, the blots were incubated with a rabbit polyclonal antiserum (1:1000) generated against purified human placental cathepsin D14 at 4°C overnight and then for two hours with 125I-labeled donkey antirabbit whole antibody (100,000 cpm per milliliter; Amersham). After washing, the blots were exposed to X-omat x-ray film (Kodak) at —70°C with the use of intensifying screens. The level of cathepsin D protein in individual tumors was determined by densitometric scanning of the 34-kd band on the autoradiographic films in a Beckman DU-7 spectrophotometer and calculated as cathepsin D units by comparison with our MCF-7 laboratory standard.
Statistical Analysis
Analyses of disease-free and overall survival were performed with use of the Kaplan–Meier method15 for dichotomized variables and Cox's partially nonparametric regression model16 17 18 for continuous variables. Tests of differences between curves were made with the log-rank test for censored survival data.19 Cox's model was also used to evaluate various combinations and interactions of prognostic factors in a multivariate manner. The patients' characteristics included in the analyses were estrogen- and progesterone-receptor status, DNA ploidy, number of positive axillary lymph nodes, size of the primary tumor, and patient's age at diagnosis. All computations were done with use of the Biomedical Computer Programs (P Series, 1985).20.
Results
Cathepsin D in Tumor Specimens
Levels of cathepsin D were measured in 397 primary breast tumors with use of the semiquantitative Western blot procedure described above. A typical Western blot of several tumors and a corresponding densitometric scan of the 34-kd region of the autoradiogram are shown in Figure 1Figure 1
Semiquantitation of Cathepsin D in Tumor Specimens by Western Blot Analysis.. Three concentrations of a constant extract of MCF-7 human breast cancer cells were included in each gel as an internal laboratory standard. Values from 0 to 1933 units were found in the 397 primary breast tumors. Cathepsin D values were significantly higher (Kruskal—Wallis P value <0.001) in the 198 specimens from patients with node-positive disease (median, 69 units) than in the 199 specimens from patients with node-negative breast cancer (median, 36 units). In both groups, the distribution was approximately log normal (Fig. 2Figure 2Distribution of the Concentration of Cathepsin D in 199 Node-Negative and 198 Node-Positive Breast Tumors.). In six cases, levels of cathepsin D were also measured in adjacent normal breast tissue; although levels ranged from 26 to 187 units in the tumors, cathepsin D levels were always low or undetectable (0 to 8 units) in normal tissue. Low values of cathepsin D in normal breast tissues were also reported by Rochefort et al.3 , 5 Cathepsin D and Clinical Outcome
Since the distribution of cathepsin D values was approximately log normal, we used the log10 of the value (after setting all zeroes to 1) as a continuous variable and examined its association with disease-free and overall survival. For the 199 patients with node-negative disease, higher cathepsin D values predicted shorter disease-free survival (P = 0.018; relative risk, 1.47 per log-unit increase) and shorter overall survival (P = 0.005; relative risk, 1.79 per log-unit increase), but the same relation did not appear for the 198 patients with node-positive disease (P = 0.68 and 0.24, respectively).
Because most prognostic factors are usually considered as dichotomized, discontinuous variables, we then selected a cutoff point for cathepsin D values to give the optimal separation between a low and high risk of relapse in the patients with node-negative disease. As shown in Figure 3Figure 3
Maximal Likelihood Determination of the Cutoff Value of Cathepsin D for Predicting Disease-free Survival in Breast Cancer.A, a considerable range of cutoff values gave a statistically significant separation of disease-free—survival possibilities. Of these, the optimal cutoff point was 75 units, which identified 32 percent of the patients as having "high" cathepsin D levels. In contrast, for patients with node-positive disease there was no cutoff value that gave a significant separation (Fig. 3B), in agreement with our earlier conclusion based on the use of cathepsin D values as a continuous variable. Analysis of overall survival gave about the same cathepsin D cutoff point as the analysis of disease-free survival for patients with node-negative disease, and no cutoff point for the node-positive group (data not shown).Cathepsin D and Other Prognostic Markers
Relations between dichotomized cathepsin D and other markers of prognosis were then determined. In the node-negative group (Table 1Table 1
Levels of Cathepsin D as Compared with Other Prognostic Factors in Patients with Node-Negative Breast Cancer.), higher levels of cathepsin D were found in patients with aneuploid tumors (P = 0.005), whereas no significant association was found between cathepsin D values and estrogen-receptor status, progesterone-receptor status, tumor size, or the age of the patient. We also examined data from the patients with node-positive disease for comparison (Table 2Table 2
Levels of Cathepsin D as Compared with Other Prognostic Factors in Patients with Node-Positive Breast Cancer.). Ploidy was not available for most of these patients, and of the other factors only the presence of positive steroid receptors was marginally associated with high levels of cathepsin D. This was not surprising, since levels of cathepsin D are increased by estrogen in some breast cancer cell lines, and a similar trend had been observed in the node-negative group (Table 1). Adjuvant therapy did not appear to introduce a bias; although the patients with node-positive disease were not all given the same adjuvant treatment, there was no significant difference between those with high cathepsin D levels and the others with respect to the proportion receiving adjuvant endocrine therapy or adjuvant chemotherapy.Cathepsin D in Multivariate Prognostic Analyses
Because in the node-positive group there was no apparent relation between high levels of cathepsin D and an increased risk of recurrence or overall survival, the rest of the analyses focused on the patients with node-negative disease. As previously noted, high levels of cathepsin D were associated with a significantly increased risk of recurrence in a univariate analysis of data from the patients with node-negative disease; the disease-free-survival curves are shown in Figure 4Figure 4
Disease-free Survival in Patients with Node-Negative Breast Cancer.A. Combining cathepsin D values with other prognostic factors in a multivariate analysis (based on 188 patients, since ploidy was not available for 11), we found that cathepsin D was the single most powerful factor for predicting disease-free survival (P = 0.0003). Comparing cathepsin D—positive with cathepsin D—negative tumors, the relative risk of recurrence was 2.6 (Table 3Table 3
Cathepsin D and Prognosis in 188 Patients with Node-Negative Breast Cancer.*). Ploidy was the second most significant factor (P = 0.009); for aneuploidy the relative risk of recurrence was 2.2. The patient's age was almost significant (P = 0.06), with younger women having a relative risk of 1.7. There were only 15 patients with diploid tumors with high levels of cathepsin D, and recurrence in this very small group was not clearly different from that in the other patients with diploidy (data not shown). In the patients with aneuploidy, however, cathepsin D values distinguished between a group with a level of recurrence similar to that of the group with diploidy and another group with far worse outcome (Fig. 4B); the five-year actuarial rate of recurrence was 22 percent in the group with diploidy and 29 percent in the group with aneuploidy and low levels of cathepsin D, but 60 percent in the group with aneuploidy and high levels of cathepsin D.Concerning overall survival, we have already noted that there was a significantly increased risk of early death (P = 0.0001) among the patients with higher levels of cathepsin D (Table 3 and Fig. 5Figure 5
Overall Survival in Patients with Node-Negative Breast Cancer.A). Aneuploidy was also associated with short overall survival (P = 0.04; Table 3). In multivariate analyses, the level of cathepsin D was the single most important variable for predicting overall survival; for high as compared with low levels, the relative risk of death was 3.9 (95 percent confidence interval, 2.1 to 7.3; P<0.0001) (Table 3). Progesterone-receptor status was the second most significant factor; for negative as compared with positive status, the relative risk of death was 2.1 (95 percent confidence interval, 1.1 to 4.0; P = 0.02). High levels of cathepsin D identified subgroups with poorer survival among patients with both positive and negative progesterone-receptor status (Fig. 5B).For both disease-free and overall survival, multivariate results were similar when cathepsin D was entered as a continuous variable (log10 cathepsin D; data not shown).
Discussion
Proteases are particularly interesting in cancer research because it has been proposed that they may play a part in the metastatic process.21 Procathepsin D acts as an autocrine mitogen on breast cancer cells and can be activated at acidic pH to degrade extracellular matrix,22 suggesting a role in mediating the effect of estrogens on tumor growth and invasion. The level of expression of 52-kd cytosolic cathepsin D has been correlated with estrogen-receptor status in breast cancer,4 but its direct clinical prognostic importance has not been established.
Cathepsin D is a ubiquitously expressed lysosomal protease. In all cell types examined to date it is synthesized as a mannose-6-phosphate—modified 52-kd glycoprotein. This transient intermediate glycoprotein is transported from the Golgi apparatus by lysosomal-targeting receptors.23 Once in the lysosome, cathepsin D is processed to a two-chain form (34 and 14 kd) that is stable and accumulates. Overexpression of the gene can cause overloading of the lysosomal-targeting pathway, resulting in constitutive secretion of the 52-kd procathepsin D. When secretion of the 52-kd form is increased, the accumulated level of the lysosomal 34-kd form also increases,24 whereas intracellular 52-kd procathepsin D is only a transient biosynthetic intermediate product. Thus, high levels of 34-kd protein may indicate the overexpression and secretion of the 52-kd precursor, which occurs in both estrogen-receptor—positive and —negative breast cancer cell lines.
We measured levels of cathepsin D in a cohort of 397 patients with primary breast cancer (198 node-positive and 199 node-negative tumors). Somewhat higher levels of mature 34-kd cathepsin D (the only form measured) were found in breast tumors that had metastasized to lymph nodes. This may suggest that cathepsin D is important for the malignant metastatic potential of breast cancer cells, but cathepsin D values failed to predict clinical outcome in these patients with node-positive disease. The reason for this is currently unclear.
In patients with node-negative disease, however, those with higher levels of cathepsin D had statistically shorter disease-free and overall survival than those with lower levels of the protein, independent of other prognostic factors. Comparing levels of cathepsin D with other established markers of prognosis, we found higher levels of cathepsin D in aneuploid tumors (P = 0.005), whereas cathepsin D values were not related to estrogen-receptor status, progesterone-receptor status, tumor size, or the age of the patient. The lack of a relation with estrogen-receptor status suggests that the role of 34-kd heavy-chain cathepsin D as a prognostic marker in breast cancer may not be related to the induction of cathepsin D expression by estrogens.
It is difficult to predict the clinical outcome of patients with node-negative breast cancer, although they are recognized in general as a group with a good prognosis. At least 70 percent of them are not expected to have a recurrence after primary treatment.25 The patients in this study did not appear to do quite as well. Perhaps our requirement of a sufficiently large specimen to determine receptors and ploidy as well as cathepsin D levels tended to exclude the smaller tumors for which the prognosis was better. Indeed, when the 199 patients with node-negative disease we describe here were compared with the remaining 2096 patients with node-negative disease in our data base (Table 4Table 4
Comparison of the 199 Patients in This Study with the Remaining 2096 Patients with Node-Negative Disease.), the present sample had a higher percentage of tumors larger than 2 cm and a reduced disease-free survival, as might be expected. No other factors differed between the two groups.There is currently no sure way of predicting which 30 percent of the patients with node-negative cancer will have recurrence of disease. An accurate battery of prognostic factors could allow the patients in whom disease is most likely to recur to receive aggressive adjuvant therapy. Current evaluation of patients with node-negative disease includes the determination of their estrogen-receptor and progesterone-receptor status to identify those at higher risk of recurrence.26 27 28 29 30 Although estrogen-receptor status and progesterone-receptor status were not statistically significant alone in our group of 199 patients with node-negative breast cancer, this may have been due to the relatively small sample.
Another marker of aggressiveness in breast tumors is ploidy (DNA content): tumors with aneuploid DNA, as measured by flow cytometry, have a higher probability of relapse.6 , 31 32 33 High levels of cathepsin D were found more often in aneuploid than in diploid tumors (41 percent vs. 21 percent), and among aneuploid tumors, higher levels of cathepsin D identified patients at extreme risk of recurrence. High levels of cathepsin D also identified patients at higher risk of death within both the progesterone-receptor—positive and —negative subgroups.
Supported by a grant (CA 30195) from the National Institutes of Health.
We are indebted to Mary Nell Baird for technical assistance, to Arthur Jennings for determining tumor-cell content in specimens, to Dr. Suzanne Fuqua for her valuable suggestions, to Judy Wenzel for data collection and analysis, to David Mascorro for computer programming, and to Sandy Montgomery for preparation of the manuscript.
Source Information
From the Department of Medicine, Divisions of Oncology and Endocrinology, University of Texas Health Science Center, San Antonio. Address reprint requests to Dr. McGuire at the Department of Medicine, Division of Oncology, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78284–7884.
- References
References
1
Rochefort
CrossRef | Web of Science | Medline2
Yonezawa
Web of Science | Medline3
Garcia
Web of Science | Medline4
Maudelonde
Web of Science | Medline5
Rochefort
CrossRef | Web of Science | Medline6
Clark
Full Text | Web of Science | Medline7
McGuire
Web of Science | Medline8
Powell
Web of Science | Medline9
Dressler
CrossRef | Web of Science | Medline10
Tandon
Web of Science | Medline11
Smith
CrossRef | Web of Science | Medline12
Laemmli
CrossRef | Web of Science | Medline13
Towbin
CrossRef | Web of Science | Medline14
Faust
CrossRef | Web of Science | Medline15
Kaplan
CrossRef | Web of Science16
Breslow
CrossRef | Web of Science17
Cox 18
Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. New York: John Wiley, 1980.
19
Mantel
Medline20
Dixon WJ, ed. BMDP statistical software. Berkeley, Calif.: University of California Press, 1983.
21
Liotta
CrossRef | Web of Science | Medline22
Briozzo
Web of Science | Medline23
Kornfeld
Web of Science | Medline24
Stein
CrossRef | Web of Science | Medline25
Harris JR, Canellos GP. Hellman S, Fisher B. Cancer of the breast. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. Vol. 2. 2nd ed. Philadelphia: J.B. Lippincott, 1985: 1119–77.
26
Crowe
CrossRef | Medline27
Bonadonna
Medline28
Pinchon
Web of Science | Medline29
McGuire
Medline30
Clark
Web of Science | Medline31
Ewers
CrossRef | Medline32
Coulson
Web of Science | Medline33
Hedley
CrossRef | Medline
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CrossRef9
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CrossRef10
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CrossRef11
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CrossRef12
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CrossRef13
E. Ioachim, E. Kitsiou, K. Charalabopoulos, A. Mitselou, N. Zagorianakou, G. Makrydimas, S. Tzioras, M. Salmas. (2003) Immunohistochemical evaluation of cathepsin D in normal, hyperplastic and malignant endometrium: Correlation with hormone receptor status c-erbB-2, p53, Rb proteins and proliferation associated indices. International Journal of Gynecological Cancer 13:3, 344-351
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CrossRef15
C.E. Rogers, R.L. Loveday, P.J. Drew, J. Greenman. (2002) Molecular prognostic indicators in breast cancer. European Journal of Surgical Oncology (EJSO) 28:5, 467-478
CrossRef16
Emad Elsobky, Mahmoud El-Baz, Mohamed Gomha, Hassan Abol-Enein, Atallah A Shaaban. (2002) Prognostic value of angiogenesis in schistosoma-associated squamous cell carcinoma of the urinary bladder. Urology 60:1, 69-73
CrossRef17
Attiqa N. Mirza, Nadeem Q. Mirza, Georges Vlastos, S. Eva Singletary. (2002) Prognostic Factors in Node-Negative Breast Cancer. Annals of Surgery 235:1, 10-26
CrossRef18
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CrossRef19
Mathie P. G. Leers, Maurius Nap. (2001) Steroid Receptor Heterogeneity in Relation to DNA Index in Breast Cancer: A Multiparameter Flow Cytometric Approach on Paraffin-Embedded Tumor Samples. The Breast Journal 7:4, 249-259
CrossRef20
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CrossRef21
Rom T. Altstock, Gideon Y. Stein, James H. Resau, Ilan Tsarfaty. (2000) Algorithms for quantitation of protein expression variation in normal versus tumor tissue as a prognostic factor in cancer: Met oncogene expression, and breast cancer as a model. Cytometry 41:3, 155-165
CrossRef22
Akiharu Dohchin, Jun-ichi Suzuki, Hideyuki Seki, Manabu Masutani, Hiroshi Shiroto, Yoshikazu Kawakami. (2000) Immunostained cathepsins B and L correlate with depth of invasion and different metastatic pathways in early stage gastric carcinoma. Cancer 89:3, 482-487
CrossRef23
H Xin. (2000) Identification of a novel aspartic-like protease differentially expressed in human breast cancer cell lines. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1501:2-3, 125-137
CrossRef24
Bernard Têtu, Jacques Brisson, Hélène Lapointe, Chang Shu Wang, Pascale Bernard, Caty Blanchette. (1999) Cathepsin D expression by cancer and stromal cells in breast cancer: an immunohistochemical study of 1348 cases. Breast Cancer Research and Treatment 55:2, 135-145
CrossRef25
Snehal Bhoola, Patricia B. DeRose, Cynthia Cohen. (1999) Ductal Carcinoma In Situ of the Breast: Frequency of Biomarkers According to Histologic Subtype. Applied Immunohistochemistry & Molecular Morphology 7:2, 108-115
CrossRef26
Wolf Müller, Wolfgang Saeger, Lars Wellhausen, Karl M. Derwahl, Christine Hamacher, Dieter K. Lüdecke. (1999) Markers of Function and Proliferation in Non-invasive and Invasive Bi- and Plurihormonal Adenomas of Patients with Acromegaly: An Immunohistochemical Study. Pathology - Research and Practice 195:9, 595-603
CrossRef27
J A Foekens, M P Look, J Bolt-de Vries, M E Meijer-van Gelder, W L J van Putten, J G M Klijn. (1999) Cathepsin-D in primary breast cancer: prognostic evaluation involving 2810 patients. British Journal of Cancer 79:2, 300-307
CrossRef28
JAMES P. CHERRY, JOHN A. MORDENTE, JOHN R. CHAPMAN, MUHAMMAD S. CHOUDHURY, HIROSHI TAZAKI, CAMILLE MALLOUH, SENSUKE KONNO. (1998) ANALYSIS OF CATHEPSIN D FORMS AND THEIR CLINICAL IMPLICATIONS IN HUMAN PROSTATE CANCER. The Journal of Urology2223-2228
CrossRef29
JAMES P. CHERRY, JOHN A. MORDENTE, JOHN R. CHAPMAN, MUHAMMAD S. CHOUDHURY, HIROSHI TAZAKI, CAMILLE MALLOUH, SENSUKE KONNO. (1998) ANALYSIS OF CATHEPSIN D FORMS AND THEIR CLINICAL IMPLICATIONS IN HUMAN PROSTATE CANCER. The Journal of Urology 160:6, 2223-2228
CrossRef30
I. Craig Henderson, Anthony J. Patek. (1998) The relationship between prognostic and predictive factors in the management of breast cancer. Breast Cancer Research and Treatment 52:1-3, 261-288
CrossRef31
Janet Moore, Michael I. Friedman, Ted Gansler, Terry L. Gramlich, Patricia B. DeRose, Dirk Hunt, Cynthia Cohen. (1998) Prognostic Indicators in Male Breast Carcinoma. The Breast Journal 4:4, 261-269
CrossRef32
P. P. Athanassiadou, P. H. Athanassiades, P. Davaris, E. I. Petrakakou, CH. I. Zerva, K. A. Kyrkou. (1998) Expression of Cathepsin D and pS2 in imprint smears of breast carcinoma. Cytopathology 9:4, 240-247
CrossRef33
Lars Wellhausen, Wolfgang Saeger, Wolf Müller, Michael Derwahl, Christiane Hamacher, Dieter K. Lüdecke. (1998) Gsα, protein kinase C, cathepsin D, growth factors, estrogen receptor-related protein, and p53 in prolactin cell adenomas and null cell adenomas of the pituitary. Endocrine Pathology 9:2, 135-148
CrossRef34
E-F. Solomayer, I.J. Diel, G.C. Meyberg, Ch. Gollan, S. Bode, D. Wallwiener, G. Bastert. (1998) Prognostic relevance of cathepsin D detection in micrometastatic cells in the bone marrow of patients with primary breast cancer. Breast Cancer Research and Treatment 49:2, 145-154
CrossRef35
K. Collett, R. Skjærven, B.O. Mæhle. (1998) The prognostic contribution of estrogen and progesterone receptor status to a modified version of the Nottingham Prognostic Index. Breast Cancer Research and Treatment 48:1, 1-9
CrossRef36
Audrey A. Rasmussen, Kevin J. Cullen. (1998) Paracrine/autocrine regulation of breast cancer by the insulin-like growth factors. Breast Cancer Research and Treatment 47:3, 219-233
CrossRef37
Seema A. Khan, Nick J. Gonchoroff, Linda E. Miller. (1997) Expression of pS2, c-erbB-2, and cathepsin D during the menstrual cycle in human breast cancers. Annals of Surgical Oncology 4:6, 462-469
CrossRef38
George E. Theodoropoulos, Dimitris Panoussopoulos, Andreas Ch. Lazaris, Basil Ch. Golematis. (1997) Evaluation of cathepsin D immunostaining in colorectal adenocarcinoma. Journal of Surgical Oncology 65:4, 242-248
CrossRef39
Joanne L. Blum, Stephen E. Jones, Joseph W. Fay, Neil Senzer, Robert G. Mennel. (1997) Guidelines for systemic therapy of early stage breast cancer. Breast Cancer Research and Treatment 43:3, 259-276
CrossRef40
Masahiko Higashiyama, Osamu Doi, Ken Kodama, Hideoki Yokouchi, Tsutomu Kasugai, Shingo Ishiguro. (1997) Influence of cathepsin D expression in lung adenocarcinoma on prognosis: Possible importance of its expression in tumor cells and stromal cells, and its intracellular polarization in tumor cells. Journal of Surgical Oncology 65:1, 10-19
CrossRef41
Uasminka Jakić Razumović, Ranka Romić Stojković, Mladen Petrovečki, Stjepan Gamulin. (1997) Correlation of two methods for determination of cathepsin D in breast carcinoma (immunohistochemistry and ELISA in cytosol). Breast Cancer Research and Treatment 43:2, 117-122
CrossRef42
Russell B. Myers, William E. Grizzle. (1997) Changes in Biomarker Expression in the Development of Prostatic Adenocarcinoma. Biotechnic & Histochemistry 72:2, 86-95
CrossRef43
Astrid Mayer, Elke Fritz, Rene Fortelny, Klaus Kofler, Heinz Ludwig. (1997) Immunohistochemical Evaluation of Cathepsin D Expression in Colorectal Cancer. Cancer Investigation 15:2, 106-110
CrossRef44
Ibrahim Barişta, Eşmen Baltali, Ibrahim H. Güllü, Nilüfer Güler, Ismail Çelik, Osman Saraçbaşi, Gülten Tekuzman, Ayşe Kars, Yavuz Özişik, Şevket Ruacan, I. Lale Atahan, Dinçer Firat. (1996) Factors Influencing the Distribution of Metastases and Survival in Metastatic Breast Carcinoma. American Journal of Clinical Oncology 19:6, 569-573
CrossRef45
KIRBY I. BLAND. (1996) Letter to the Editor. Annals of Surgery 224:5, 687
CrossRef46
Mehrdad Nadji, Manuel Fresno, Mehdi Nassiri, Gregory Conner, Agustin Herrero, Azorides R Morales. (1996) Cathepsin D in host stromal cells, but not in tumor cells, is associated with aggressive behavior in node-negative breast cancer. Human Pathology 27:9, 890-895
CrossRef47
Michael R Emmert-Buck. (1996) Cathepsin D and prognosis in breast cancer: One piece of a larger puzzle?. Human Pathology 27:9, 869-871
CrossRef48
Anastassia Hatzoglou, Efstathia Bakogeorgou, Chryssa Hatzoglou, Pierre-Marie Martin, Elias Castanas. (1996) Antiproliferative and receptor binding properties of α- and β-casomorphins in the T47D human breast cancer cell line. European Journal of Pharmacology 310:2-3, 217-223
CrossRef49
Gunnar B. Kristensen, Ruth Holm, Vera M. Abeler, Claes G. Tropé. (1996) Evaluation of the prognostic significance of cathepsin D, epidermal growth factor receptor, and c-erbB-2 in early cervical squamous cell carcinoma: An immunohistochemical study. Cancer 78:3, 433-440
CrossRef50
Myriam Polette, Philippe Birembaut. (1996) Matrix Metalloproteinases in Breast Cancer. The Breast Journal 2:3, 209-220
CrossRef51
Maurizio Maurizi, Giovanni Almadori, Gabriella Cadoni, Giovanni Scambia, Fabrizio Ottaviani, Gabriella Ferrandina, Gaetano Paludetti, Giovanni D'Abramo, Salvatore Mancuso. (1996) Cathepsin D concentration in primary laryngeal cancer: Correlation with clinico-pathological parameters, EGFR status and prognosis. International Journal of Cancer 69:2, 105-109
CrossRef52
Judd W. Moul, Susan J. Maygarden, Joy L. Ware, James L. Mohler, Paul D. Maher, Noah S. Schenkman, Chi K. Ho. (1996) Cathepsin D and Epidermal Growth Factor Receptor Immunohistochemistry does not Predict Recurrence of Prostate Cancer in Patients Undergoing Radical Prostatectomy. The Journal of Urology982-985
CrossRef53
Judd W. Moul, Susan J. Maygarden, Joy L. Ware, James L. Mohler, Paul D. Maher, Noah S. Schenkman, Chi K. Ho. (1996) Cathepsin D and Epidermal Growth Factor Receptor Immunohistochemistry does not Predict Recurrence of Prostate Cancer in Patients Undergoing Radical Prostatectomy. The Journal of Urology 155:3, 982-985
CrossRef54
Piero L. Alo, Paolo Visca, Adele Marci, Antonella Mangoni, Claudio Botti, Ugo Di Tondo. (1996) Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. Cancer 77:3, 474-482
CrossRef55
G Scambia. (1995) Significance of Cathepsin-D expression in uterine tumours. European Journal of Cancer 31:9, 1449-1454
CrossRef56
Laura E. Janocko, Joseph F. Lucke, David W. Groft, Kathryn A. Brown, Charles A. Smith, Agnese A. Pollice, Sarita G. Singh, Robert Yakulis, Robert J. Hartsock, Stanley E. Shackney. (1995) Assessing sequential oncogene amplification in human breast cancer. Cytometry 21:1, 18-22
CrossRef57
D Simon. (1995) Cathepsin D-like aspartyl protease activity mediates the degradation of tissue-type plasminogen activator/plasminogen activator inhibitor-1 complexes in human monocytes. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1268:2, 143-151
CrossRef58
Andrew J. Dickinson, Stephen B. Fox, Paul V. Newcomb, Raj A. Persad, Gary N. Sibley, Adrian L. Harris. (1995) An Immunohistochemical and Prognostic Evaluation of Cathepsin D Expression in 105 Bladder Carcinomas. The Journal of Urology 154:1, 237-241
CrossRef59
Andrew J. Dickinson, Stephen B. Fox, Paul V. Newcomb, Raj A. Persad, Gary N. Sibley, Adrian L. Harris. (1995) An Immunohistochemical and Prognostic Evaluation of Cathepsin D Expression in 105 Bladder Carcinomas. The Journal of Urology237-241
CrossRef60
Liangzhong Xu, Weiping Zhu, Taiming Zhang, Aiping Jing, Zhenzhou Shen. (1995) The expression of Cathepsin-D,C-erbB-2 and EGFR in breast cancer and its correlation to lymphatic metastasis. Chinese Journal of Cancer Research 7:2, 97-102
CrossRef61
Morton K. Schwartz. (1995) Tissue cathepsins as tumor markers. Clinica Chimica Acta 237:1-2, 67-78
CrossRef62
Kirby I. Bland. (1995) The Emerging Importance of Molecular Biology in the Therapy of Breast Carcinoma. The Breast Journal 1:3, 125-127
CrossRef63
Mohammed K.K. El-Tanani, Chris D. Green. (1995) Oestrogen-induced genes, pLIV-1 and pS2, respond divergently to other steroid hormones in MCF-7 cells. Molecular and Cellular Endocrinology 111:1, 75-81
CrossRef64
George E. Theodoropoulos, Dimitris Panoussopoulos, Basil Ch. Golematis, Andreas Ch. Lazaris, Panagiotis Davaris. (1995) Significance of estrogen receptors and cathepsin D tissue detection in gastric adenocarcinoma. Journal of Surgical Oncology 58:3, 176-183
CrossRef65
D. MILIARAS, A. KAMAS, H. KALEKOU. (1995) Angiogenesis in invasive breast carcinoma: is it associated with parameters of prognostic significance?. Histopathology 26:2, 165-169
CrossRef66
G. Sfrio, C. Zampatti, M. Ceppi. (1995) Spindle and giant cell carcinoma of the urinary bladder: a clinicopathological light microscopic and immunohistochemical study. British Journal of Urology 75:2, 167-172
CrossRef67
James T. Wu, Mark E. Astill, Shane D. Gagon, Lynn Bryson. (1995) Measurement of c-erbb-2 proteins in sera from patients with carcinomas and in breast tumor tissue cytosols: Correlation with serum tumor markers and membrane-bound oncoprotein. Journal of Clinical Laboratory Analysis 9:3, 151-165
CrossRef68
Raymond M. Shaheen, Slobodan Miseljic, David L. Doering, James L. Wittliff. (1995) Comparison of cathepsin d determinations in human carcinomas by enzyme immunoassay and immunoradiometric assay. Journal of Clinical Laboratory Analysis 9:6, 351-358
CrossRef69
Michael Stierer, Harald Rosen, Renate Weber, Hanns Hanak, Leo Auerbach, J
rgen Spona, Heinz T
CrossRef70
Slobodan Miseljic, Susan Galandiuk, Stephen D. Myers, James L. Wittliff. (1995) Expression of urokinase-type plasminogen activator and plasminogen activator inhibitor in colon disease. Journal of Clinical Laboratory Analysis 9:6, 413-417
CrossRef71
A. J. DICKINSON, S. B. FOX, R. A. PERSAD, J. HOLLYER, G. N. A. SIBLEY, A. L. HARRIS. (1994) Quantification of angiongenesis as an independent predictor of prognosis in invasive bladder carcinomas. British Journal of Urology 74:6, 762-766
CrossRef72
N. Vigneswaran, S. Müller, P. Derose, C. Cohen. (1994) Cathepsin-D and tumor associated antigen DF3 in salivary gland neoplasia. Pathology - Research and Practice 190:12, 1174-1184
CrossRef73
Michael J. Duffy, David Reilly, E. McDermott, Niall O'Higgins, James J. Fennelly, Peter A. Andreasen. (1994) Urokinase plasminogen activator as a prognostic marker in different subgroups of patients with breast cancer. Cancer 74:8, 2276-2280
CrossRef74
Teresa Castiglioni, Maria J. Merino, Boris Elsner, Tamara T. Lah, Bonnie F. Sloane, Michael R. Emmert-Buck. (1994) Immunohistochemical analysis of cathepsins D, B, and L in human breast cancer. Human Pathology 25:9, 857-862
CrossRef75
Robert D. Cardiff. (1994) Cathepsin D and breast cancer: Useful?. Human Pathology 25:9, 847-848
CrossRef76
M. Chambon, H. Rochefort, J. P. Brouillet, P. Baldet, T. Maudelonde, X. Rebillard, J. Guiter. (1994) Cathepsin D cytosolic assay and immunohistochemical quantification in human prostate tumors. The Prostate 24:6, 320-325
CrossRef77
E.E. Chouinard, V. Chen, T.J. D'Souza, R.H. Riddell. (1994) Reproducibility of pathological grading in breast cancer. The Breast 3:2, 124-129
CrossRef78
E. George Elias, Charles M. Suter, Sally D. Brown, Barbara S. Buda, Debra A. Vachon. (1994) Survival differences between black and white women with breast cancer. Journal of Surgical Oncology 55:1, 37-41
CrossRef79
M Krulik. (1994) Les traitements adjuvants du cancer du sein précoce sans atteinte ganglionnaire. La Revue de Médecine Interne 15:3, 210-215
CrossRef80
Edward G. Mansour, Peter M. Ravdin, Lynn Dressier. (1994) Prognostic factors in early breast carcinoma. Cancer 74:S1, 381-400
CrossRef81
F. Jänicke, H. Graeff. (1993) Möglichkeiten und Grenzen der adjuvanten systemischen Therapie des Mammakarzinoms unter Berücksichtigung von Selektionsparametern. Archives of Gynecology and Obstetrics 254:1-4, 755-765
CrossRef82
Santo Marsigliante, Antonella Muscella, Vito Ciardo, Stewart Barker, Giuseppe Leo, Valerie Baker, Ali Mottaghi, Gavin P. Vinson, Carlo Storelli. (1993) Enzyme-linked immunosorbent assay of HER-2/neu gene product (p185) in breast cancer: its correlation with sex steroid receptors, cathepsin D and histologic grades. Cancer Letters 75:3, 195-206
CrossRef83
P. Kristen, H. Caffier. (1993) Kathepsin D bei Ovarialtumoren. Archives of Gynecology and Obstetrics 254:1-4, 952-954
CrossRef84
ROSELLA SILVESTRINI. (1993) Biological Markers for Designing Clinical Protocols. Annals of the New York Academy of Sciences 698:1 Breast Cancer, 271-278
CrossRef85
Fritz Jänicke, Manfred Schmitt, Lothar Pache, Kurt Ulm, Nadia Harbeck, Heinz Höfler, Henner Graeff. (1993) Urokinase (uPA) and its inhibitor PAI-1 are strong and independent prognostic factors in node-negative breast cancer. Breast Cancer Research and Treatment 24:3, 195-208
CrossRef86
Peter M. Ravdin. (1993) Evaluation of cathepsin D as a prognostic factor in breast cancer. Breast Cancer Research and Treatment 24:3, 219-226
CrossRef87
Jerzy Jankun, Hollis W. Merrick, Peter J. Goldblatt. (1993) Expression and localization of elements of the plasminogen activation system in benign breast disease and breast cancers. Journal of Cellular Biochemistry 53:2, 135-144
CrossRef88
Bernard Tětu, Chantal C??té, Sonia Brisson, Nancy Roberge, Jacques Brisson, Diane Potvin. (1993) Prognostic significance of cathepsin-D expression in node-positive breast carcinoma: An immunohistochemical study. International Journal of Cancer 55:3, 429-435
CrossRef89
Thierry Métayé, Christine Millet, Jean-Louis Kraimps, Brigitte Aubouin, Jacques Barbier, François Bégon. (1993) Estrogen receptors and cathepsin d in human thyroid tissue. Cancer 72:6, 1991-1996
CrossRef90
J. HURLIMANN, S. GEBHARD, F. GOMEZ. (1993) Oestrogen receptor, progesterone receptor, pS2, ERD5, HSP27 and cathepsin D in invasive ductal breast carcinomas. Histopathology 23:3, 239-248
CrossRef91
D.W. Visscher, F.H. Sarkar, W. Sakr, J. Crissman. (1993) Immunohistologic analysis of invasive phenotype in breast carcinoma. Pathology - Research and Practice 189:8, 867-872
CrossRef92
Colette Charpin, Bénédicte Devictor, Pascal Bonnier, Lucile Andrac, Marie Noëlle Lavaut, Claude Allasia, Lucien Piana. (1993) Cathepsin D immunocytochemical assays in breast carcinomas: Image analysis and correlation to prognostic factors. The Journal of Pathology 170:4, 463-470
CrossRef93
Shin-Ichi Yamashita, Jun-Ichi Yamashita, Kiyoshi Sakamoto, Kazuo Inada, Yasunari Nakashima, Kazuya Murata, Tetsushi Saishoji, Koichi Nomura, Michio Ogawa. (1993) Increased expression of membrane-associated phospholipase A2 shows malignant potential of human breast cancer cells. Cancer 71:10, 3058-3064
CrossRef94
Patricia L. Kandalaft, Karen L. Chang, Chul W. Ahn, S. Thomas Traweek, Parula Mehta, Hector Battifora. (1993) Prognostic significance of immunohistochemical analysis of cathepsin D in low-stage breast cancer. Cancer 71:9, 2756-2763
CrossRef95
Garth R. Anderson, Daniel L. Stoler. (1993) Anoxia, wound healing, VL30 elements, and the molecular basis of malignant conversion. BioEssays 15:4, 265-272
CrossRef96
Pascal Pujol, Thierry Maudelonde, Jean-Pierre Daures, Philippe Rouanet, Jean-Paul Brouillet, Henri Pujol, Henri Rochefort. (1993) A prospective study of the prognostic value of cathepsin D levels in breast cancer cytosol. Cancer 71:6, 2006-2012
CrossRef97
F. M. Tumminello, R. J. Bernacki, N. Gebbia, G. Leto. (1993) Pepstatins: Aspartic proteinase inhibitors having potential therapeutic applications. Medicinal Research Reviews 13:2, 199-208
CrossRef98
Santo Marsigliante, Leonardo Resta, Giuseppe Leo, Daniela Mazzotta, Rita d'Amore, Luciana Biscozzo, Carlo Storelli. (1993) Expression of cathepsin D in malignant and in the corresponding non-malignant node-negative laryngeal samples: correlation with receptors for androgen, glucocorticoid, oestrogen and progesterone. Cancer Letters 68:2-3, 135-142
CrossRef99
Suzanne Rogers, Christopher A. Day, Stephen B. Fox. (1993) Expression of cathepsin D and estrogen receptor in male breast carcinoma. Human Pathology 24:2, 148-151
CrossRef100
Dutzu Rosner, Warren W. Lane. (1993) Predicting recurrence in axillary-node negative breast cancer patients. Breast Cancer Research and Treatment 25:2, 127-139
CrossRef101
Louis P. Pertschuk, Joseph G. Feldman, Dong S. Kim, Kamran Nayeri, Karen Byer Eisenberg, Anne C. Carter, William T. Thelmo, Zheng Tian Rhong, Peter Benn, Abraham Grossman. (1993) Steroid hormone receptor immunohistochemistry and amplification of c-myc protooncogene relationship to disease-free survival in breast cancer. Cancer 71:1, 162-171
CrossRef102
Henry F. Frierson. (1993) Grade and flow cytometric analysis of ploidy for infiltrating ductal carcinomas. Human Pathology 24:1, 24-29
CrossRef103
Markku Miettinen. (1993) Immunohistochemistry in Tumour Diagnosis. Annals of Medicine 25:3, 221-233
CrossRef104
William L. McGuire, Atul K. Tandon, D. Craig Allred, Gary C. Chamness, Peter M. Ravdin, Gay M. Clark. (1992) Prognosis and treatment decisions in patients with breast cancer without axillary node involvement. Cancer 70:S4, 1775-1781
CrossRef105
J.G.M. Klijn, P.M.J.J. Berns, M. Bontenbal, J. Alexieva-Figusch, J.A. Foekens. (1992) Clinical breast cancer, new developments in selection and endocrine treatment of patients. The Journal of Steroid Biochemistry and Molecular Biology 43:1-3, 211-221
CrossRef106
Brian C.-S. Liu, Robert E. Weiss, Jeffrey N. Gordon, Michael J. Droller. (1992) Biology of metastasis: Clinical implications. Seminars in Surgical Oncology 8:5, 267-273
CrossRef107
Desforges, Jane F., , McGuire, William L., Clark, Gary M., . (1992) Prognostic Factors and Treatment Decisions in Axillary-Node-Negative Breast Cancer. New England Journal of Medicine 326:26, 1756-1761
Full Text108
Henderson, I. Craig, . (1992) Breast Cancer Therapy — The Price of Success. New England Journal of Medicine 326:26, 1774-1775
Full Text109
Rodrigo Arriagada, Lars Erik Rutqvist, Lambert Skoog, Hemming Johansson, Andrew Kramar. (1992) Prognostic factors and natural history in lymph node-negative breast cancer patients. Breast Cancer Research and Treatment 21:2, 101-109
CrossRef110
Ann D. Thor, Frederick C. Koerner, Susan M. Edgerton, William C. Wood, Michael A. Stracher, Laurent H. Schwartz. (1992) pS2 expression in primary breast carcinomas: Relationship to clinical and histological features and survival. Breast Cancer Research and Treatment 21:2, 111-119
CrossRef111
M. J. Duffy. (1992) The role of proteolytic enzymes in cancer invasion and metastasis. Clinical & Experimental Metastasis 10:3, 145-155
CrossRef112
Harvey D. Preisler, Azra Raza. (1992) The role of emerging technologies in the diagnosis and staging of neoplastic diseases. Cancer 69:S6, 1520-1526
CrossRef113
Morton K. Schwartz. (1992) Enzymes as prognostic markers and therapeutic indicators in patients with cancer. Clinica Chimica Acta 206:1-2, 77-82
CrossRef114
N.P.M. Sacks, L.C. Barr, S.M. Allan, M. Baum. (1992) The role of axillary dissection in operable breast cancer. The Breast 1:1, 41-49
CrossRef115
S. Mark Redwood, Brian C.-S. Liu, Robert E. Weiss, Derrick E. Hodge, Michael J. Droller. (1992) Abrogation of the invasion of human bladder tumor cells by using protease inhibitor(s). Cancer 69:5, 1212-1219
CrossRef116
Steven Lehrer, Eva Levine, Penny Savoretti, Joan Cropley, Charles Botstein, Hee Kyung Song, Lynda Mandell, Brenda Shank. (1992) Past pregnancy is associated with axillary node involvement in women with breast cancer. Cancer 69:4, 981-983
CrossRef117
Angelo Paradiso, Anita Mangia, Mario Correale, Ines Abbate, Giovanni Ferri, Adriano Piffanelli, Laura Catozzi, Dino Amadori, Angela Riccobon, Angela Riccobon. (1992) Cytosol cathepsin-D content and proliferative activity of human breast cancer. Breast Cancer Research and Treatment 23:1-2, 63-70
CrossRef118
Edward G. Mansour. (1992) The value of prognostic factors in selecting node-negative breast cancer patients for adjuvant therapy. Journal of Surgical Oncology 49:2, 73-75
CrossRef119
Y. Remvikos, M. Gerbault-Seureau, H. Magdelénat, M. Prieur, B. Dutrillaux. (1992) Proliferative activity of breast cancers increases in the course of genetic evolution as defined by cytogenetic analysis. Breast Cancer Research and Treatment 23:1-2, 43-49
CrossRef120
Henri Rochefort. (1992) Biological and Clinical Significance of Cathepsin D in Breast Cancer. Acta Oncologica 31:2, 125-130
CrossRef121
Yong Yang, Geoffrey D. Chisholm, Fouad K. Habib. (1992) The distribution of PSA, cathepsin-D, and pS2 in BPH and cancer of the prostate. The Prostate 21:3, 201-208
CrossRef122
S. Safe, B. Astroff, M. Harris, T. Zacharewski, R. Dickerson, M. Romkes, L. Biegel. (1991) 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and Related Compounds as Antioestrogens: Characterization and Mechanism of Action. Pharmacology & Toxicology 69:6, 400-409
CrossRef123
J.P. Brouillet, B. Hanslick, T. Maudelonde, M.T. Pivat, J. Grenier, F. Blanc, H. Rochefort. (1991) Increased plasma cathepsin D concentration in hepatic carcinoma and cirrhosis but not in breast cancer. Clinical Biochemistry 24:6, 491-496
CrossRef124
Catherine Malet, Alexandra Vacca, Frédérique Kuttenn, Pierre Mauvais-Jarvis. (1991) 17β-estradiol dehydrogenase (E2DH) activity in T47D cells. The Journal of Steroid Biochemistry and Molecular Biology 39:5, 769-775
CrossRef125
E.C. Kohn. (1991) Invasion and metastasis: Biology and clinical potential. Pharmacology & Therapeutics 52:2, 235-244
CrossRef126
T. E. Witzig, N. J. Gonchoroff, T. Therneau, D. T. Gilbertson, L. E. Wold, C. Grant, J. Grande, J. A. Katzmann, D. L. Ahmann, J. N. Ingle. (1991) DNA content flow cytometry as a prognostic factor for node-positive breast cancer. The role of multiparameter ploidy analysis and specimen sonication. Cancer 68:8, 1781-1788
CrossRef127
Moïse Namer, Alain Ramaioli, Xavier Fontana, Marie-Christine Etienne, Michel Héry, Alain Jourlait, Gérard Milano, Marc Frenay, Eric François, Françoise Lapalus. (1991) Prognostic value of total cathepsin D in breast tumors. Breast Cancer Research and Treatment 19:2, 85-93
CrossRef128
Michael A. Bookman, Lori J. Goldstein, Richard M. Scher. (1991) Medical management of early-stage breast cancer. Current Problems in Cancer 15:4, 161-232
CrossRef129
P. Briozzo, J. Badet, F. Capony, I. Pieri, P. Montcourrier, D. Barritault, H. Rochefort. (1991) MCF7 mammary cancer cells respond to bFGF and internalize it following its release from extracellular matrix: A permissive role of cathepsin D. Experimental Cell Research 194:2, 252-259
CrossRef130
Jeffrey L. Berenberg. (1991) Response to treatment of breast cancer. Breast Cancer Research and Treatment 18:S1, S147-S155
CrossRef131
Marc J. Van de Vijver, Roel Nusse. (1991) The molecular biology of breast cancer. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1072:1, 33-50
CrossRef132
M. Grant, G. Blijham, M. Schemper, A. Reiner, G. Reiner, J. Spona, M. Reynders, B. Schutte, C. Asche, G. Steger, R. Jakesz. (1991) Der prognostische Stellenwert der Flowzytometrie beim Mammakarzinom. European Surgery 23:2, 43-48
CrossRef133
LaSalle D. Leffall. (1991) Progress in cancer. The American Journal of Surgery 161:2, 272-278
CrossRef134
J. A. Søreide, O. A. Lea, S. Kvinnsland. (1991) Cytosol protein content and prognosis in operable breast cancer. Breast Cancer Research and Treatment 20:1, 25-32
CrossRef135
AVRUM BLUMING, WILLIAM J. M. HRUSHESKY. (1991) The Effect of Surgical Timing within the Fertility Cycle on Breast Cancer Outcome. Annals of the New York Academy of Sciences 618:1 Temporal Cont, 277-291
CrossRef136
Lance A Liotta, Patricia S Steeg, William G Stetler-Stevenson. (1991) Cancer metastasis and angiogenesis: An imbalance of positive and negative regulation. Cell 64:2, 327-336
CrossRef137
Lisa Biegel, Stephen Safe. (1990) Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on cell growth and the secretion of the estrogen-induced 34-, 52- and 160-kDa proteins in human breast cancer cells. The Journal of Steroid Biochemistry and Molecular Biology 37:5, 725-732
CrossRef138
Eva M. Valverius, Thierry Velu, Vidya Shankar, Fortunato Ciardiello, Nancy Kim, David S. Salomon. (1990) Over-expression of the epidermal growth factor receptor in human breast cancer cells fails to induce an Estrogen-independent phenotype. International Journal of Cancer 46:4, 712-718
CrossRef139
A. MUNRO NEVILLE. (1990) Functional immunocytopathology and the diagnosis of bone marrow micrometastases. Cytopathology 1:4, 223-231
CrossRef140
James A. Robb. (1990) The future anatomic pathology laboratory for molecular diagnosis and prognosis: Circa 1990–95. Clinical Biochemistry 23:4, 295-299
CrossRef141
A. Munro Neville. (1990) Are breast cancer axillary node micrometastases worth detecting?. The Journal of Pathology 161:4, 283-284
CrossRef142
Henri Rochefort. (1990) Cathepsin D in breast cancer. Breast Cancer Research and Treatment 16:1, 3-13
CrossRef143
(1990) Cathepsin D in Breast Cancer. New England Journal of Medicine 322:23, 1673-1674
Full Text144
Ingle, James N., . (1990) Assessing the Risk of Recurrence in Breast Cancer. New England Journal of Medicine 322:5, 329-331
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