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© 2000 American Society for Clinical Oncology Hormonal Predictors of Prostate Cancer: A Meta-AnalysisFrom the Divisions of Endocrinology and Oncology, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, and Harvard School of Public Health, Boston, MA. Address reprint requests to Christos S. Mantzoros, MD, Division of Endocrinology, RN 325, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Ave, Boston, MA 02215; email cmantzor{at}bidmc.harvard.edu
PURPOSE: Although there is strong circumstantial evidence that androgens are implicated in the etiology of prostate cancer, epidemiologic investigations have failed to demonstrate consistently that one or more steroid hormones are implicated. In contrast, recent epidemiologic studies unequivocally link serum insulin-like growth factor 1 (IGF-1) levels with risk for prostate cancer. METHODS: We have performed the first meta-analysis of all previously published studies on hormonal predictors of risk for prostate cancer. RESULTS: A meta-analysis restricted to studies that performed mutual adjustment for all measured serum hormones, age, and body mass index indicated that men whose total testosterone is in the highest quartile are 2.34 times more likely to develop prostate cancer (95% confidence interval, 1.30 to 4.20). In contrast, levels of dihydrotestosterone and estradiol do not seem to play a role of equal importance. The only study that provides multivariably adjusted sex hormone–binding globulin data indicates that this binding protein is inversely related to prostate cancer risk (odds ratio, 0.46; 95% confidence interval, 0.24 to 0.89). Finally, all three studies that examined the role of serum IGF-1 have consistently demonstrated a positive and significant association with prostate cancer risk that is similar in magnitude to that of testosterone. CONCLUSION: Men with either serum testosterone or IGF-1 levels in upper quartile of the population distribution have an approximately two-fold higher risk for developing prostate cancer.
THERE IS STRONG circumstantial evidence that androgens are implicated in the pathogenesis of prostate cancer.1,2 Androgens are essential for the growth of the prostate gland, can induce malignant proliferation of prostate cancer cells in vitro, and can produce prostate cancer in experimental animals in vivo. Moreover, androgen deficiency before adulthood prevents development of prostate cancer, and androgen ablation is associated with prostate cancer remission.3-5 Despite these observations, epidemiologic investigations have failed to consistently demonstrate that circulating levels of one or more sex hormones and/or their binding protein are implicated in the etiology of prostate cancer.5-12 Thus, the distinct possibility exists that sex steroids do not play a major role in the etiology of prostate cancer. Perhaps the effect of sex steroids in the serum is mediated by differences in androgen receptor expression or function (such as the number of CAG repeats in the transactivating domain) or intracellular androgen levels. It is also possible that the nonsignificant results of some epidemiologic studies may reflect their relatively small size or the lack of adjustment for confounding factors. In this meta-analysis, we systematically reviewed all previously published studies to determine whether, after controlling for potential confounding factors such as age and body mass index, as well as mutually for other steroid hormones, androgens contribute to the risk for prostate cancer. This analysis was not limited by small sample size. Importantly, this is the first meta-analysis of its kind. In contrast to the conflicting data of studies on androgens, three recent studies have unequivocally linked circulating levels of insulin-like growth factor 1 (IGF-1) with risk for developing prostate cancer.13-15 A secondary aim of this study was to compare the magnitude of association between risk for prostate cancer and androgens to that between prostate cancer and circulating levels of IGF-1.
Study Identification and Selection Studies were identified by a computerized search of the MEDLINE and CANCERLIT databases from January 1966 to July 1998 with the search headings of "prostate neoplasms," "prostate cancer," "17-ketosteroids," "adrenal cortex hormones," "androgens," "androstenedione," "dehydroepiandosterone," "prasterone," "sex hormones," "stanolone," "testicular hormones," "testosterone," "DHT," "SHBG," "estradiol," "IGF-1," "insulin-like growth factor," "IGF BP-3," "insulin-like growth factor binding protein 3," and "dihydrotestosterone." The search was limited to human studies only. A manual search of the bibliographies of all retrieved articles was performed. Furthermore, an expert in cancer epidemiology and authors of the retrieved articles were contacted to ensure that all possible studies were identified for review. All studies had to describe clearly the study population, including age and ethnicity; criteria for selecting cases and controls; serum collection, storage, and analysis techniques; and length of follow-up from study entry to diagnosis of prostate cancer. Furthermore, the diagnosis of prostate cancer had to be confirmed histologically. Finally, controls or noncases had to be concurrent and free of any known cancer. We excluded reviews, editorials, case reports, duplicate reports, or reports of data later presented in full (one study9 ), and studies that measured hormones other than testosterone, dihydrotestosterone (DHT), sex hormone–binding globulin (SHBG), and estradiol (one study16 ). However, these studies were searched for relevant references. Overall, we identified 28 studies on the role of sex hormones, and three studies13-15 on the role of IGF-1 on prostate cancer. First, we reviewed systematically all prospectively collected data. More specifically, we performed a primary meta-analysis of existing cohort and case-control studies that are nested in a cohort study (Table 1) on the role of sex steroids in the etiology of prostate cancer. To be included in the primary meta-analysis, reports had to be either a prospective cohort or nested case-control studies. We included only prospective studies for the following reasons: (1) we wanted to examine the effect of serum sex hormones on the development of prostate cancer without the potential confounding effect of coexisting prostate cancer, a problem inherent in case-control studies; and (2) most case-control studies also have not controlled for confounding factors and have not performed mutual adjustment for serum steroids.
At present, the literature includes five prospective cohort studies.8-11,17 However, only three8,9,11 are included in this meta-analysis for estimates of unadjusted and two for estimates of adjusted effect estimates of sex hormones and prostate cancer (Table 2). We excluded from formal meta-analysis the articles by Barrett-Connor et al and Guess et al because these studies did not present data on all three sex steroids of interest. This is important because multivariate adjustment for these variables, which are interrelated, could not be performed for inclusion in the final meta-analysis. However, we present descriptive characteristics and unadjusted mean differences of all five studies listed in Table 1.
In addition, we reviewed all case-control studies on the role of sex hormones on prostate cancer. These 23 studies on the role of sex hormones are included in a secondary analysis focusing on case-control studies. Finally, we reviewed the two case-control studies14,15 and the one nested case-control study13 that focused on the role of IGF-1 in prostate cancer and list the relevant effect estimates in Table 3. These data are included to provide a comparison to the androgen studies. A formal meta-analysis of these three studies would be redundant because all three reported similar and statistically significant results (see Results).
Data Extraction We assembled the following information for each case-control or cohort study: year of publication, study design, age range of the study population, number of participants enrolled, study population source, years of follow-up from initial blood sample to diagnosis of prostate cancer, serum hormone levels, and both adjusted and unadjusted odds ratios (ORs) for development of prostate cancer (comparing highest quartile of serum hormones to the lowest). Because we based this meta-analysis on ORs and not absolute hormone levels, potential differences in assays used in previously published studies do not affect the validity of this study. Two readers independently extracted the data, with adjudication by a third if disagreement arose. When data were missing from any of the studies, the authors were contacted for the missing data. For the study by Hsing and Comstock,8 adjusted and unadjusted data were supplied by the primary author (A.H.), whereas for the studies by Barrett-Connor et al10 and Guess et al,17 the primary authors did not supply any data. Thus, these studies were not included in the final meta-analysis because of missing relevant data.
Statistical Analysis ORs for the development of prostate cancer from the included studies were combined by means of the DerSimonian and Laird random effects method to obtain summary estimates of the loge(OR).18 We also estimated the corresponding 95% confidence intervals (CIs). We used the formula X ± 1.96(S + S2A)0.5, where X represents the combined loge(OR), S is the within trial variance, and S2A is the DerSimonian and Laird estimate of the among-trial variance. We present both the unadjusted and adjusted (for other sex hormones, age, and body mass index) summary estimates of the OR for each serum hormone. A secondary analysis of the case-control studies was performed. These 23 case-control studies were not included in the primary meta-analysis because, as discussed, they were retrospective and did not report ORs for the development of prostate cancer. However, for these studies, we also used the vote count method for each hormone to determine if the serum levels were higher, lower, or not different between cases and controls. Although this is not an optimal analysis, we believed that these studies could not be combined by the more sophisticated methods we used for the cohort studies because of relatively poor and variable study design, the great disparity of the methods used for selecting controls, the different effect estimates used for data presentation, the lack of mutual adjustment of measured steroids, and the concern for the confounding effect of prostate cancer on hormone levels.
Cohort and Case-Control Studies Nested in Cohort Studies on the Role of Androgens The characteristics of the three cohort and nested case-control studies included in the primary meta-analysis are listed in Table 1. Table 2 lists the ORs and the corresponding 95% CIs from each of the individual studies along with the summary ORs derived using the DerSimonian and Laird method. After adjustment for the other serum hormones, age, and body mass index, men whose total serum testosterone is in the highest quartile are 2.34 times more likely to develop prostate cancer than those in the lowest quartile (95% CI, 1.30 to 4.20), whereas neither DHT nor estradiol levels seem to be significantly associated with the development of prostate cancer (Table 2). Interestingly, based on the one study that provides multivariate adjusted SHBG data,11 men who have the highest SHBG levels are less likely to develop prostate cancer relative to those with the lowest levels (adjusted OR, 0.46; 95% CI, 0.24 to 0.89). This suggests that circulating bioavailable testosterone is more important in the development of prostate cancer than total testosterone.
Case-Control Studies on the Role of Androgens The majority of the studies found no statistically significant difference between the cases and control groups with respect to the three plasma hormones and SHBG. In studies that analyzed testosterone levels, 57% (17 of 28) showed no difference in serum testosterone levels between cases and controls, 23% showed lower levels in cases, and only 20% (six of 28) showed higher levels. Only one11 of the eight studies that measured SHBG levels demonstrated lower levels in cases than in controls, but two studies29,37 found elevated levels. Although the majority of studies showed no difference for both DHT and estradiol levels, in each instance there were two studies21,39 that had significantly lower levels in the group with prostate cancer compared with controls, and no study found higher levels. In summary, this secondary analysis shows no consistent findings of available case-control studies.
Studies on the Role of IGF-1
Despite strong circumstantial evidence indicating that androgens play a role in the etiology of prostate cancer, data from previously published epidemiologic studies have shown inconsistent and often conflicting results.5,6 These findings have been attributed to limitations inherent in case-control investigations, including selection bias. It has also been suggested that prostatectomy or advanced prostate cancer per se may alter circulating hormone concentrations.7 In addition, control for confounding factors and mutual adjustment for steroid levels has not been performed in most published case-control studies. Several investigators used the nested case-control study design, using prediagnostic sera to study the role of sex hormones as predictors of risk for developing prostate cancer.8-12 One reported a positive but not significant association with testosterone,8 whereas another reported a significant inverse association with DHT.9 A third study reported a significant positive association with testosterone, a significant inverse association with SHBG, and a nonsignificant inverse association with DHT after these hormones were mutually adjusted.11 Finally, one study reported no association of prostate cancer with any of the studied hormones.12 Faced with these conflicting results, we performed the first meta-analysis of the previously published studies on the hormonal predictors of risk for prostate cancer to determine whether either small study size and/or failure to perform a multivariate analysis of interrelated hormonal variables (ie, testosterone, DHT, and estradiol) could have accounted for the conflicting results. This analysis focused on the hormones that have previously attracted the attention of most investigators, ie, the main circulating androgens (testosterone and DHT) and the main circulating estrogen (estradiol). The effect of the binding protein that regulated tissue availability of estrogens and androgens (SHBG) could not be adequately studied because the relevant data are not available in most of the primary studies, and free testosterone has not usually been measured. In a meta-analysis model that does not involve multivariate adjustment for the studied hormones, no steroid hormone seems to be significantly associated with the development of prostate cancer. However, because serum sex steroids are interrelated, adjustment for mutual confounding is of critical importance. Thus, we entered in our meta-analysis model available data only from all studies that have performed multivariate adjustment for all three steroids. This model shows that circulating testosterone concentrations are positively and significantly related to developing prostate cancer. The extent to which circulating hormonal concentrations reflect intraprostatic sex steroid interconversion and action is not clearly known. It is currently believed that circulating androgens act in prostate cells either directly or after being converted to more potent androgens such as DHT inside the cells. Thus, concentrations of circulating sex steroids reflect some measure of substrate availability to the prostate gland. Our study provides evidence that increased testosterone levels affect risk for developing prostate cancer by either increasing substrate availability for intraprostatic DHT production and/or resulting in direct androgenic action on prostate epithelial cells.41 This is consistent with recent experimental evidence that indicates that differences in levels of androgenic precursors and, more specifically, testosterone levels, rather than differences in 5-alpha reductase activity per se, are responsible for the observed differences in prostate cancer incidence between white and Chinese subjects.42 This study has also evaluated the circulating concentrations of DHT, a hormone considered to be a potent androgen. It seems that either circulating DHT is not representative of intraprostatic hormone levels or that DHT does not play a major role in the etiology of prostate cancer. The variation in serum concentrations of this hormone may not accurately reflect intraprostatic activity, because DHT is produced from testosterone by two distinct isoforms of 5-alpha reductase, only one of which (type 2a) is the predominant intraprostatic form.43 Obviously, therefore, differences in 5-alpha reductase enzymatic activity must be important in mediating intracellular levels. In addition, recent experimental evidence indicates that a negative feedback mechanism, the exact nature of which has not yet been clearly elucidated, may reciprocally regulate DHT and testosterone concentrations both intraprostatically and in the serum.41,44 This feedback loop may be important if testosterone is responsible for an increased risk of developing the disease. Because logistic considerations make an epidemiologic study using more direct markers of intraprostatic androgen activity almost impossible to conduct, the results of an ongoing randomized, double-blind, placebo-controlled trial on the effect of a 5-alpha reductase inhibitor in preventing prostate cancer may further elucidate the relationship between testosterone, DHT, and prostate cancer. Finally, results of recent studies unequivocally indicate that IGF-1 levels seem to be a significant predictor of developing prostate cancer, a finding consistent with available evidence from both in vivo and in vitro studies. It is important to note that the overall level of risk for patients in the highest quartile for IGF-1 is similar in magnitude with that of men in the highest quartile of testosterone. Prostate cancer cells produce IGF-1 and its binding proteins45-47 and express IGF-1 receptors.45,46 In vitro activation of these receptors induces proliferation of prostate cancer cells,48 whereas antisense mRNA to the IGF-1 receptor suppresses tumor growth and invasion.49 Furthermore, it is possible that IGF-1 may affect prostate cancer cells by interacting with androgens.50 This review has certain limitations, including the fact that the primary meta-analysis on the role of androgen levels is based on only three of five assessable studies for unadjusted and two for adjusted effect estimates. Two studies had to be excluded because the first17 measured only testosterone, and because several steroids are interrelated, mutual adjustment for sex hormone levels is necessary to reach reliable conclusions; and in the second study,10 the data were not provided in such a way that they could be included in the final meta-analysis. Despite excluding these two studies, this meta-analysis is based on evaluation of the majority of the previously studied cases (461 of 624 cases for the unadjusted data and 320 of 624 cases for the adjusted data). In addition, all cases included in this meta-analysis had been confirmed by both clinical and pathologic criteria, and controls were examined systematically for the absence of subclinical prostate cancer to avoid bias from these sources. Additionally, all studies analyzed used prediagnostic sera from incident prostate cancer cases and used similar analytic methods to determine circulating concentrations of the studied hormones. Assay variability introduced by possible sample degradation of stored prediagnostic sera is minimal because the studied hormones are particularly stable in frozen sera stored under the conditions described in the studies evaluated. Finally, we have used ORs for this meta-analysis, which further minimized methodologic differences of the included studies and provided a method to compare the effect of androgens with that of IGF-1. In summary, this meta-analysis of all high-quality studies supports a role for circulating testosterone and IGF-1 in predicting risk for prostate cancer. More specifically, men with either testosterone or IGF-1 levels in the upper quartile of the population distribution have an approximately two-fold higher risk for developing prostate cancer, an increased risk comparable only to that of men with a first-degree relative with prostate cancer.
1. van Steenbrugge GJ, Schroder FH: Androgen-dependent human prostate cancer in nude mice: The PC-82 tumor model. Am J Clin Oncol 11: S8-12, 1988 (suppl 2) 2. Smolev JK, Coffey DS, Scott WW: Experimental models for the study of prostatic adenocarcinomas. J Urol 118:216-220, 1977[Medline]
3.
Henderson BE, Ross BK, Pike MC, et al: Endogenous hormones as a major factor in human cancer. Cancer Res 42:3232-3239, 1982
4.
Hsing AW: Hormones and prostate cancer: Where do we go from here? J Natl Cancer Inst 88:1093-1095, 1996
5.
Nomura AM, Kolonel LN: Prostate cancer: A current perspective. Epidemiol Rev 13:200-207, 1991 6. Andersson SO, Adami H-O, Bergstrom R, et al: Serum pituitary and sex steroid hormone levels in the etiology of prostatic cancer: A population based case-control study. Cancer 68:97-102, 1993 7. Meikle AW, Smith JA, Stringham JD: Production, clearance, and metabolism of testosterone in men with prostatic cancer. Prostate 10:25-31, 1987[Medline] 8. Hsing AW, Comstock GW: Serological precursors of cancer: Serum hormones and risk of subsequent prostate cancer. Biomarkers Prev 2:27-32, 1993
9.
Nomura A, Heilbrun LK, Stemmermann GN, et al: Prediagnostic serum hormones and the risk of prostate cancer. Cancer Res 48:3515-3517, 1988
10.
Barrett-Connor E, Garland C, McPhillips JB, et al: A prospective, population based study of androstendione, estrogens and prostatic cancer. Cancer Res 50:169-173, 1990
11.
Gann PH, Hennekens CH, Ma J, et al: Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst 88:1118-1126, 1996 12. Nomura A, Stemmermann GN, Chyou P-A, et al: Serum androgens and prostate cancer. Cancer Epidemiol Biomarkers Prev 5:621-625, 1996[Abstract]
13.
Chan J, Stampfer M, Giovannucci E, et al: Plasma insulin-like growth factor-1 and prostate cancer risk: A prospective study. Science 279:563-566, 1998 14. Mantzoros C, Tzonou A, Signorello L, et al: Insulin-like growth factor 1 in relation to prostate cancer and benign prostatic hyperplasia. Br J Cancer 76:1115-1118, 1997[Medline]
15.
Wolk A, Mantzoros C, Anderson S-O, et al: Insulin-like growth factor 1 in relation to prostate cancer: A population-based case-control study in Sweden. J Natl Cancer Inst 90:911-915, 1998 16. Comstock GW, Gordon GB, Hsing AW: The relationship of serum dehydroepiandrosterone and its sulfate to subsequent cancer of the prostate. Cancer Epidemiol Biomarkers Prev 2:219-221, 1993[Abstract]
17.
Guess HA, Friedman GD, Sadler MC, et al: 5-alpha reductase activity and prostate cancer: A case-control study using stored sera. Cancer Epidemiol Biomarkers Prev 6:21-24, 1997 18. DerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin Trial 7:177-188, 1986[Medline] 19. Gustafsson O, Norming U, Gustaffson S, et al: Dihydrotestosterone and testosterone levels in men screened for prostate cancer: A study of a randomized population. Br J Urol 77:433-440, 1996[Medline] 20. Carlstrom K, Stege R: Testicular and adrenocortical function in men with prostatic cancer and in healthy age-matched controls. Br J Urol 79:427-431, 1997[Medline] 21. Ahluwalia B, Jackson MA, Jones GW, et al: Blood hormone profiles in prostate cancer patients in high-risk and low-risk populations. Cancer 48:2267-2273, 1981[Medline] 22. Bartsch W, Steins P, Becker H: Hormone blood levels in patients with prostatic carcinoma and their relation to the type of carcinoma growth differentiation. Eur Urol 3:47-52, 1977[Medline] 23. Bartsch W, Horst HJ, Becker H, et al: Sex hormone binding globulin capacity, testosterone, 5-alpha dihydrotestosterone, oestradiol and prolactin in plasma of patients with prostatic carcinoma under various types of hormonal treatment. Acta Endocrinol 85:650-664, 1977 24. Drafta D, Proca E, Zamfir V, et al: Plasma steroids in benign hypertrophy and carcinoma of the prostate. J Steroid Biochem 17:689-693, 1982[Medline] 25. Ghanadian R, Puah CM, O’Donoghue EPN: Serum testosterone and dihydrotestosterone in carcinoma of the prostate. Br J Cancer 39:696-699, 1979[Medline] 26. Hammond G, Kontturi M, Vihko P, et al: Serum steroids in normal males and patients with prostatic diseases. Endocrinol 9:113-121, 1978 27. Harper ME, Peeling WB, Cowley T, et al: Plasma steroid and protein hormone concentrations in patients with prostate cancer before and during oestrogen therapy. Acta Endocrinol 81:409-426, 1976
28.
Hill P, Wynder EL, Garbaczewski L, et al: Effect of diet on plasma and urinary hormones in South African black men with prostatic cancer. Cancer Res 42:3864-3869, 1982 29. Hoisaeter PA, Haukaas S, Bakke A, et al: Blood hormone levels related to stages and grades of prostatic cancer. Prostate 3:375-381, 1982[Medline] 30. Hsing A, Comstock G: Serum hormone and risk of subsequent prostate cancer. Am J Epidemiol 130:829, 1989 (abstr) 31. Hulka BS, Hammond JE, Difernando G, et al: Serum hormone levels among patients with prostatic carcinoma or benign prostatic hypertrophy and clinic controls. Prostate 11:171-182, 1987[Medline] 32. Jackson MA, Kovi J, Heshmat MY, et al: Characterization of prostatic carcinoma among blacks: A comparison between a low-incidence area, Ibadan, Nigeria, and a high-incidence area, Washington, DC. Prostate 1:185-205, 1980[Medline] 33. Jacobi GH, Rathgen GH, Altwein JE: Serum prolactin and tumors of the prostate: Unchanged basal levels and lack of correlation to serum testosterone. J Endocrinol 3:15-18, 1980 34. Levell MJ, Rowe E, Glashan RW, et al: Free testosterone in carcinoma of the prostate. Prostate 7:363-367, 1985 35. Meikle AW, Stanish W: Familial prostatic cancer risk and low testosterone. Metabol 54:1104-1108, 1982 36. Meikle AW, Smith JA, Stringham JD: Estradiol and testosterone metabolism and production in men with prostatic cancer. J Steroid Biochem 33:19-24, 1989[Medline] 37. Ranikko FS, Adlercreutz H: Plasma estradiol, free testosterone, sex hormone binding globulin capacity and prolactin in benign prostatic hyperplasia and prostate cancer. Prostate 4:223-229, 1983[Medline] 38. Ross R, Bernstein L, Lobo R, et al: 5-Alpha reductase activity and risk of prostate cancer among Japanese and US white and black males. Lancet 339:887-889, 1992[Medline] 39. Saroff J, Kirdani RY, Chu TM, et al: Measurements of prolactin and androgens in patients with prostatic diseases. Oncology 37:46-52, 1980[Medline] 40. Zumoff B, Levin J, Strain GW, et al: Abnormal levels of plasma hormones in men with prostate cancer: Evidence toward a "two-disease" theory. Prostate 3:579-588, 1982[Medline] 41. Montie JE, Pienta K: Review of the role of androgenic hormones in the epidemiology of prostate cancer and benign prostatic hyperplasia. Urology 43:892-898, 1994[Medline]
42.
Santner SJ, Albertson B, Zhang G-Y, et al: Comparative rates of androgen production and metabolism in Caucasian and Chinese subjects. J Clin Endocrinol Metab 83:2104-2109, 1998 43. Wilson JD: The intranuclear metabolism of testosterone in the accessory organs of reproduction. Recent Prog Horm Res 26:309-336, 1990 44. Geller J: Approach to chemoprevention of prostate cancer. Endocrinol Metab 80:717-719, 1995
45.
Cohen P, Peehl DM, Lamson G, et al: Insulin like growth factors (IGF), IGF receptors and IGF binding proteins in primary culture of prostate epithelial cells. J Clin Endocrinol Metab 73:401-407, 1991 46. Kimura G, Kasuaya J, Giannini S, et al: Insulin like growth factor (IGF) system components in human prostatic cancer cell lines: LnCaP, DU 145, PC-3 cells. Int J Urol 3:39-46, 1996[Medline]
47.
Pietrzkowski Z, Mulholand G, Gomella L, et al: Inhibition of growth of prostatic cancer cell lines by peptide analogues of insulin-like growth factor 1. Cancer Res 53:1102-1106, 1993 48. Angelloz-Nicoud P, Binoux M: Autocrine regulation of cell proliferation by the insulin like growth factor (IGF) and IGF binding protein 3 protease system in a human prostate carcinoma cell line (PC-3). Endocrinology 136:5485-5492, 1995[Abstract]
49.
Burfeind P, Chernicky CL, Rininsland F, et al: Antisense RNA to the type insulin like growth factor receptor suppresses tumor growth and prevents invasion by rat prostate cancer cells in vivo. Sci U S A 93:7263-7268, 1996 50. Culig Z, Hobish A, Cronauer MV, et al: Androgen receptor activation of prostatic tumor cell lines by insulin like growth factor 1, keratinocyte growth factor and epidermal growth factor. Eur Urol 27:45-47, 1995 (suppl 2) Submitted June 9, 1999; accepted September 13, 1999.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
