Mammary Fibroadenoma Research Articles

CD44 exon 6 expression as a possible early prognostic factor in primary node negative breast carcinoma.

Breast cancer is the most common female malignancy affecting approximately one woman in eight. Many attempts have been made to define markers which may have potential clinical applications in diagnosis as well as therapy. New isoforms of CD44 with alternative spliced exons have recently been described. We studied the expression of CD44 exon 6 using a semi-quantitative RT-PCR reaction on a panel of 25 normal breast specimens, 10 mammary fibroadenomas, eight cystic samples and 52 primary breast tumors. Significant correlation was found between CD44 exon 6 expression and the overall survival of the N-M-population, P = 0.032, (logrank test by Mantel's method). The same result was also observed for the disease-free survival, P = 0.000002 (logrank test by Mantel's method). CD44 exon 6 expression, as detected by our RT-PCR-based method, might be a useful prognostic indicator of metastasis in breast cancer. However, these preliminary results need to be confirmed by later retrospective and prospective studies on a larger number of patients.

Bilateral testicular large-cell calcifying Sertoli cell tumor and recurrent cardiac myxoma in a patient with Carney’s complex

Large-cell calcifying Sertoli cell tumors are exceedingly rare testicular tumors which can be distinguished from pure Sertoli cell tumors by distinctive microscopic features and multifocal and bilateral calcifications [1]. We describe the characteristic sonographic appearance of the tumor with pathologic correlation. This tumor also constitutes one of the conditions of Carney's complex [2], which includes cardiac and skin myxomas, myxoid mammary fibroadenomas, spotty skin pigmentation, primary pigmented nodular adrenocortical disease, pituitary adenoma and unusual testicular tumors, especially large-cell calcifying Sertoli cell tumor. We report the case of a 10-year-old boy with four of the above conditions. Recognition of this complex is important as cardiac myxomas can lead to lethal complications. Because of a tendency for familial occurrence, family members should be screened carefully [3].

A need to subclassify mammary fibroadenoma into “Complex” and “noncomplex” subtypes?

A need to subclassify mammary fibroadenoma into “Complex” and “noncomplex” subtypes?

FDG uptake, tumor proliferation and expression of glycolysis associated genes in animal tumor models

To determine the influence of tumor cell proliferation and changes in the genetic program in malignant cells on the fluorodeoxyglucose (FDG) uptake we performed PET studies in several animal tumors: spontaneous mammary fibroadenoma, chemically-induced mammary adenocarcinoma and Dunning prostate adenocarcinoma. The expression of the glucose transporter (GLUT1) and of hexokinase (Hk) was measured using 32P-labeled cDNA probes and densitometry. Furthermore the proliferative activity was determined with one-dimensional flow cytometry.The FDG uptake and the proliferation parameters were not correlated. The normalized amounts of GLUT and Hk mRNA were lower in spontaneous fibroadenomas and prostate tumors than in chemically induced mammary. The FDG uptake was correlated to GLUT1 expression with r = 0.83 and to Hk expression with r = 0.77. Multiple regression analysis revealed a relation of FDG uptake to GLUT1 and HK with r = 0.87. Our results show that the FDG uptake in our study was related not to differences in proliferation, but rather to differences in the transcription of glycolysis associated genes.

Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinase produced by breast carcinomas

A cDNA coding for a new human matrix metalloproteinase (MMP) has been cloned from a cDNA library derived from a breast tumor. The isolated cDNA contains an open reading frame coding for a polypeptide of 471 amino acids. The predicted protein sequence displays extensive similarity to the previously known MMPs and presents all the structural features characteristic of the members of this protein family, including the well conserved PRCGXPD motif, involved in the latency of the enzyme and the zinc-binding domain (HEXGHXXXXXHS). In addition, this novel human MMP contains in its amino acid sequence several residues specific to the collagenase subfamily (Tyr-214, Asp-235, and Gly-237) and lacks the 9-residue insertion present in the stromelysins. According to these structural characteristics, the MMP described herein has been tentatively called collagenase-3, since it represents the third member of this subfamily, composed at present of fibroblast and neutrophil collagenases. The collagenase-3 cDNA was expressed in a vaccinia virus system, and the recombinant protein was able to degrade fibrillar collagens, providing support to the hypothesis that the isolated cDNA codes for an authentic collagenase. Northern blot analysis of RNA from normal and pathological tissues demonstrated the existence in breast tumors of three different mRNA species, which seem to be the result of the utilization of different polyadenylation sites present in the 3'-noncoding region of the gene. By contrast, no collagenase-3 mRNA was detected either by Northern blot or RNA polymerase chain reaction analysis with RNA from other human tissues, including normal breast, mammary fibroadenomas, liver, placenta, ovary, uterus, prostate, and parotid gland. On the basis of the increased expression of collagenase-3 in breast carcinomas and the absence of detectable expression in normal tissues, a possible role for this metalloproteinase in the tumoral process is proposed.

Spontaneous Neoplasms in Control Wistar Rats

Spontaneous Neoplasms in Control Wistar Rats. Walsh, K. M., and Poteracki, J. (1994). Fundam. Appl. Toxicol. 22, 65-72.Neoplastic data on 1370 control Wistar rats from 10 carcinogenicity bioassays done between 1980 and 1990 were reviewed. Mean percentage survival at 104 weeks was 58% for males and 59% for females. A total of 1857 neoplasms were diagnosed in 466 (68%) male and 582 (85%) female rats; 1390 were benign and 467 were malignant (12% with metastasis). Seventy-four percent of all neoplasms were in endocrine and reproductive systems. Most common neoplasms (affecting more than 7% of either sex) were pituitary adenoma (27.7% males; 55.0% females), mammary fibroadenoma (1.0% males; 25.3% females), mammary adenocarcinoma (1.0% males; 13.1% females), adrenal cortical adenoma (8.3% males; 9.3% females), and endometrial stromal polyp (9.6% females). Fourteen neoplasms affecting 2 to 6% of either sex included adrenal pheochromocytoma, thyroid C cell adenoma, thyroid follicular adenoma, pancreatic islet cell adenoma, lymphoma, histiocytic sarcoma, thymoma, hepatic adenoma, pancreatic acinar adenoma, mammary adenoma, dermal fibroma, astrocytoma, testicular interstitial cell tumor, and ovarian granulosa cell tumor. Remaining neoplasms were seen in less than 2% of animals.

Human carcinogenic risk assessment based on hormonal effects in a carcinogenicity study in rats with the antifungal agent, fluconazole

Fluconazole is an orally active bis-triazole antifungal agent that acts by selective inhibition of lanosterol 14 alpha-demethylase, a key enzyme for maintenance of the fungal cell wall. It is not genotoxic. In a 2 year carcinogenicity study in Sprague-Dawley rats, fluconazole decreased mammary fibroadenomas in females and adrenal pheochromocytomas in males, and increased hepatic adenomas in males. The pattern of these changes is explicable in terms of a hormonal imbalance, corroborated in other studies with fluconazole in rats by changes in the weights of hormone-sensitive organs and circulating levels of 17 beta-estradiol. The decreases in mammary tumors are probably a consequence of aromatase inhibition by fluconazole at high dose levels. The tumor effects observed in this study are extremely unlikely to be of relevance to humans, since the hormone effects observed in this study do not occur in humans treated with therapeutic dose levels of fluconazole. This study illustrates the importance of seeking a mechanistic interpretation of rodent tumor findings, which may then be assessed for its relevance to the clinical use of a drug.

Studies on leukemia developing spontaneously in an inbred family of rats.

This study is a continuation of our recently reported observations on leukemia and lymphomas developing spontaneously in a subline of Sprague-Dawley rats bred by brother-to-sister mating in our laboratory. The previous preliminary report described our observations made in the course of the initial 12 generations of our leukemic subline. The current study reviews the data collected during 8 additional generations and results of experimental and morphologic studies. There was no problem in transmitting the spontaneously developing leukemia by inoculation of suspensions of leukemic cells into newborn or very young suckling Sprague-Dawley rats. Attempts to transmit the disease by inoculation of cell-free, filtered leukemic extracts gave thus far positive results only in one experiment in which two of six inoculated rats developed leukemia and a third one developed an angiosarcoma on the neck. In six additional experiments, of a total of 37 rats inoculated with leukemic filtrates, none developed leukemia and 9 females developed mammary fibroadenomas. Reviews of microscopic slides of blood and of sections of lymphoid tumors, livers, spleens, kidneys, and fragments of bone marrow of the leukemic animals are discussed as well as electron microscopic studies.

Bioassay for carcinogenicity of rotenone in female wistar rats

Rotenone, a pesticide extracted from the Derris root, consistently was reported by a series of investigators to have induced mammary fibroadenomas in female Wistar rats when administered ip or by gavage in a sunflower (SF) oil or SF oil:chloroform vehicle. In contrast, no less than eight bioassays done in other laboratories with rotenone or rotenone-containing powders have given consistently negative carcinogenic results when different strains or species and different modes or vehicles of administration have been used. However, these studies were not designed to address the biological reproducibility of the positive data. Thus, the present study was designed to simulate conditions of the positive studies and to investigate a possible cocarcinogenic interaction between rotenone and chloroform. Each of eight treatment groups was assigned 72 weanling female Wistar rats. Groups were (1) untreated, (2) needle puncture, (3) SF oil:10% chloroform (SF oil:chloroform), (4) 1.0 mg/kg rotenone in SF oil:chloroform, (5) 2.0 mg/kg rotenone in SF oil:chloroform, (6) SF oil, (7) 1.0 mg/kg rotenone in SF oil, and (8) 2.0 mg/kg rotenone in SF oil. Rats were injected ip 5 days a week for 8 weeks (42 injection days) and subsequently held for 16 months. The appearance of palpable tissue masses was recorded; over 50 tissues from each rat were histologically evaluated. There were no statistically significant differences in overall or individual tumor incidences among control and rotenone-treated groups. Specifically, neither incidence nor time-to-palpation of mammary fibroadenoma significantly differed among control and rotenone-treated groups, regardless of the vehicle of administration. Thus, rotenone was not carcinogenic, and rotenone and chloroform did not interact to produce a carcinogenic effect in female Wistar rats in the current study. Thus, previous reports of carcinogenic activity were not reproducible under similar experimental conditions.

Fat, frail and dying young: survival, body weight and pathology of the Charles River Sprague-Dawley-derived rat prior to and since the introduction of the VAFR variant in 1988.

Trends in survival and body weight were evaluated in 2140 control Sprague-Dawley-derived [Crl: COBS-CD(SD)BR and Crl: COBS-VAF CD(SD)BR] rats used for 24-month rat carcinogenicity studies between 1979 and 1991. Body weight and survival were remarkably stable in the CD-COBS rats used during 1979-1987: at 24 months, the mean survival in males was 68 +/- 5%, and 60 +/- 5% in females. With the CD-COBS-VAF rat, a variant of the CD-COBS strain used between 1988 and 1991, the survival at 24 months dropped to 41 +/- 3% in males, and 44 +/- 7% in females compared to the CD-COBS. The CD-COBS-VAF rat had a significantly reduced life span (P < 0.001 at 24 months), a significant increase in mean body weight (males at 6 months: 672 +/- 24 g vs. 536 +/- 6 g; females: 359 +/- 7 g vs 308 +/- 3 g; P < 0.001) and food consumption (males at 6 months: 31.3 +/- 3.3 vs. 25.4 +/- 2.1 g d-1; females: 22.0 +/- 2.7 g v. 20.3 +/- 2.0 g d-1; P < 0.001). CD-COBS-VAF rats which failed to survive up to study termination had individual body weights at 3, 6 and 12 months which were significantly higher (P < 0.001) than those which survived until 24 months. Our historical data base of control rats (CD-COBS and CD-COBS-VAF) in carcinogenicity studies revealed a significant (males: P < 0.001); females: P < 0.01) and inverse linear relation between mean 3-month body weight and 24-month survival. When compared to CD-COBS animals, CD-COBS-VAF rats showed an increase in the incidence of pituitary tumours in males, mammary fibroadenomas in females, an increase in the incidence of severity of glomerulonephrosis, and a greater incidence of animals which died without any obvious pathology. It is concluded that, in our Sprague-Dawley substrains, both the individual and the group mean body weights in early adult life appear predictive for the individual and group life expectancy. The decrease in longevity in the CD-COBS-VAF rat is principally due to disease and degeneration processes associated with fast growth and high body weight.

Bioassay for Carcinogenicity of Rotenone in Female Wistar Rats

Rotenone, a pesticide extracted from the Derris root, consistently was reported by a series of investigators to have induced mammary fibroadenomas in female Wistar rats when administered ip or by gavage in a sunflower (SF) oil or SF oil:chloroform vehicle. In contrast, no less than eight bioassays done in other laboratories with rotenone or rotenone-containing powders have given consistently negative carcinogenic results when different strains or species and different modes or vehicles of administration have been used. However, these studies were not designed to address the biological reproducibility of the positive data. Thus, the present study was designed to simulate conditions of the positive studies and to investigate a possible cocarcinogenic interaction between rotenone and chloroform. Each of eight treatment groups was assigned 72 weanling female Wistar rats. Groups were (1) untreated, (2) needle puncture, (3) SF oil: 10% chloroform (SF oil:chloroform), (4) 1.0 mg/kg rotenone in SF oil:chloroform, (5) 2.0 mg%kg rotenone in SF oil:chloroform, (6) SF oil, (7) 1.0 mg/kg rotenone in SF oil, and (8) 2.0 mg/kg rotenone in SF oil. Rats were injected ip 5 days a week for 8 weeks (42 injection days) and subsequently held for 16 months. The appearance of palpable tissue masses was recorded; over 50 tissues from each rat were histologically evaluated. There were no statistically significant differences in overall or individual tumor incidences among control and rotenone treated groups. Specifically, neither incidence nor time-to-palpation of mammary fibroadenoma significantly differed among control and rotenone-treated groups, regardless of the vehicle of administration. Thus, rotenone was not carcinogenic, and rotenone and chloroform did not interact to produce a carcinogenic effect in female Wistar rats in the current study. Thus, previous reports of carcinogenic activity were not reproducible under similar experimental conditions.

2-year Toxicity Study of Doxylamine Succinate in the Fischer 344 Rat

Doxylamine succinate, a commonly used antihistamine, was administered as an admixture in the feed to groups of male and female Fischer 344 rats at dose levels of 0, 500, 1000, and 2000 parts per million (ppm) (based on free amine) for 65 weeks (9 per group) or two years (48 per group). There were no significant treatment-related differences in survival in either sex. Compared to controls, final body weights of rats in the 2000 ppm group were reduced 8.4% and 22.8% in males and females, respectively. Treatment-related, non-neoplastic lesions were found primarily in the liver and parotid salivary gland. Liver lesions consisted of fatty change and degeneration in both sexes; hyperplasia (resulting from degeneration due to leukemia) and atypical cells in males; and hypertrophy, chronic inflammation, and mixed cell foci in females. Both sexes exhibited a treatment-related increase in cytoplasmic alteration in the salivary glands. Liver neoplasms were found only in the highest dose group of male rats. The trend test was significant (p ≤ 0.05) for increased incidence of hepatocellular adenoma and carcinoma with increasing doses of doxylamine, but the increased incidence of either lesion in the high dose group was not significant compared to that in controls. However, when animals with carcinoma or adenoma were combined, the trend test remained significant (p ≤ 0.01), and the incidence of the highest dose group was significantly increased (p ≤ 0.05) over that in controls. No treatment-related increase in neoplasms was found in females, but doxylamine produced a marked dose-related decrease in mammary fibroadenomas. Although not statistically significant, a very rare pineal gland tumor was found in 1 male and 1 female rat in the 2000 ppm group.

Requirement for the adenovirus type 9 E4 region in production of mammary tumors.

Oncogenic viruses demonstrating a strict tropism for the mammary gland provide special opportunities to study the susceptibility of this tissue to neoplasia. In rats, human adenovirus type 9 (Ad9) elicits mammary fibroadenomas that are similar to common breast tumors in women, as well as phyllodes-like tumors and mammary sarcomas. By constructing recombinant adenoviruses between Ad9 and Ad26 (a related nontumorigenic virus), it was shown that the Ad9 E4 region was absolutely required to produce these mammary tumors. This indicates that an adenovirus gene located outside the classic transforming region (E1) can significantly influence the in vivo oncogenicity of an adenovirus. Consistent with a direct role in mammary gland oncogenesis, the Ad9 E4 region also exhibited transforming properties in vitro. Therefore, the Ad9 E4 region is a viral oncogene specifically involved in mammary gland tumorigenesis.

Neoplasms and Related Proliferative Lesions in Control Sprague-Dawley Rats from Carcinogenicity Studies. Historical Data and Diagnostic Considerations

Historical data are presented for neoplasms and related proliferative lesions from 1,170 Sprague-Dawley rats that served as controls in 9 carcinogenicity (2 year) studies conducted in the Safety Evaluation Facility of Ciba-Geigy Corporation, Summit, New Jersey. The most common neoplasm was pituitary adenoma, which occurred in 62.2% of the male and 84.7% of the female rats. Incidences of other neoplasms that occurred in more than 6.0% of the rats were, for males, benign pheochromocytoma (19.0%), cutaneous keratoacanthoma (7.9%), pancreatic islet cell adenoma (7.5%), benign testicular interstitial cell tumor (6.5%), and thyroid C-cell adenoma (6.5%). For females these incidences were mammary fibroadenoma (31.3%), mammary adenocarcinoma (16.8%), and mammary adenoma (6.5%). Focal cortical hypertrophy/cystic degeneration of the adrenal, a focal nonneoplastic lesion of zona fasciculata cells that often degenerate into large cysts, was present in 23.4% of all male and 82.7% of all female rats. Criteria for the differential diagnoses of selected neoplasms and related lesions are presented.

Spontaneous neoplasms in aged control Fischer 344 rats

Neoplastic lesions in untreated F-344 rats (740 males and 740 females) used as controls in carcinogenicity studies were evaluated and tabulated. The incidence of spontaneous tumors was 84.3% in the males and 76.2% in the females. In males, the most common neoplasms were testicular interstitial cell tumors (79.5%) followed by mononuclear cell leukemia/lymphomas (30.5%), pituitary adenomas (20.5%), pancreatic islet cell adenomas (6.5%), thyroid c-cell adenomas (5.7%), pheochromocytomas (5.7%), skin fibromas (3.2%), keratoacanthomas (1.9%), and thyroid follicular cell adenomas (1.9%). In females, the most common neoplasms were pituitary adenomas (30.3%) followed by mononuclear cell leukemia/lymphomas (20.5%), endometrial polyps (14.1%), mammary fibroadenomas (11.1%), thyroid c-cell adenomas (5.1%), mammary adenomas (1.9%), skin fibromas (1.1%), and clitoral carcinomas (1.1%). A variety of less common neoplasms were also observed in various other organs.

Caffeine inhibits development of benign mammary gland tumors in carcinogen-treated female Sprague-Dawley rats

The purpose of this study was to assess the influence of caffeine on the incidence of benign mammary tumors in carcinogen (DMBA) treated female Sprague-Dawley rats. Four different animal models were used in these studies, i.e., the administration of DMBA to: [1] 55 day old virgin rats; [2] 53 day old ovariectomized, estrogen treated virgin rats; [3] 135 day old virgin rats and [4] 135 day old parous rats. A high incidence of benign mammary fibroadenomas was observed in each of the four animal models. In addition, in the estrogen treated ovariectomized animals, a high incidence of secretory mammary gland cysts was observed. Caffeine (500 mg/L drinking water) was administered daily throughout the study commencing 3-31 days after carcinogen treatment. Caffeine treatment significantly (P less than 0.05 to P less than 0.001) reduced the incidence of benign mammary fibroadenomas in the 55 day old virgin rat model (P less than 0.01), in the 53 day old estrogen treated ovariectomized virgin rat model (P less than 0.05 to P less than 0.001) and in the 135 day old virgin rat model (P less than 0.05). The number of benign mammary fibroadenomas was reduced by caffeine in the 135 day old parous rat model but this reduction was not significant (P less than 0.10). In addition, in the estrogen treated ovariectomized virgin rat model, caffeine significantly (P less than 0.05 to P less than 0.001) reduced the incidence of mammary gland cysts. Caffeine treatment either increased or had no significant effect on body weight gains, depending upon the animal model.(ABSTRACT TRUNCATED AT 250 WORDS)

Human adenovirus type 9-induced rat mammary tumors

Following subcutaneous inoculation of newborn Wistar-Furth rats with human adenovirus type 9 (Ad9), 16 of 16 female and 0 of 11 male rats developed mammary tumors. Tumor-positive animals usually developed tumors in multiple glands. Histopathological analyses indicated that three general categories of tumor could be identified. Mammary fibroadenomas were the most common tumor type encountered, but phyllodeslike tumors and solid sarcomas were also frequently found. In situ hybridization and immunohistochemical techniques established that benign fibroadenomas were derived from mammary fibroblasts (collagen type I- and vimentin-positive cells) and that malignant tumors were derived from myoepithelial cells (collagen type IV-, vimentin-, and muscle-specific actin-positive cells). The fact that mammary tumors were limited to female rats suggested that female hormones are essential for tumor growth and development. In this regard, ovariectomy of Ad9-infected female rats prevented tumor development, while subsequent diethylstilbestrol (DES) treatment elicited tumor formation. In addition, Ad9-infected and castrated male rats which received DES also developed mammary tumors. Established male mammary tumors regressed when DES treatment was stopped and reappeared after DES treatment was resumed. Together, these results indicate that estrogen is required for both initiation and maintenance of Ad9-induced mammary tumors. Southern blot analysis of high-molecular-weight tumor DNA showed that mammary tumor cells contained single or multiple integrated copies of the entire Ad9 genome. RNase protection experiments established that estrogen receptor as well as Ad9 E1a and E4 mRNAs were expressed in mammary tumors, but Ad9 E3 and, surprisingly, E1b mRNAs were not expressed at detectable levels.

Chronic toxicity studies with thiram in Wistar rats and beagle dogs

Groups of 64 male and 64 female Wistar rats were given thiram at constant dietary doses of 0, 3, 30, and 300 ppm (0, 0.1, 1.2, and 11.6 mg/kg/day for males and 0, 0.1, 1.4, and 13.8 mg/kg/day for females) for 104 weeks. Eight males and eight females in each group were killed after Weeks 13, 26, and 52. For the dog study, four male and four female beagle dogs were allotted to each group and treated with the compound at 0, 0.4, 4, and 40 mg/kg/day for 104 weeks. The dogs in the 40 mg/kg/day group had severe toxic signs, including nausea or vomiting, salivation, and occasional clonic convulsion, and all were subjected to unscheduled necropsy before Day 203 of treatment. The dogs also had ophthalmological changes such as fundal hemorrhage, miosis, and desquamation of the retina which were consistent with the retinal lesions shown by histopathology. The rats of the high-dose group had retarded growth with a slightly decreased food intake. Anemia was evident in highdose female rats and in middle- and high-dose dogs. Liver failure in male and female dogs and kidney damage in female dogs were detected in middle- and high-dose groups by blood biochemistry and/or histopathology. Regressive changes of the sciatic nerve accompanied by atrophy of the calf muscle were seen in female rats of the high-dose group but not in male rats. In high-dose rats, progression of myocardial lesions of the heart and chronic nephrosis of the kidney were depressed in males and females, respectively. Female rats of the middle- and high-dose groups had decreased occurrences of mammary fibroadenoma and decreased development of skin masses.

Chronic Toxicity Studies with Thiram in Wistar Rats and Beagle Dogs

Chronic Toxicity Studies with Thiram in Wistar Rats and Beagle Dogs. Maita, K., Tsuda, S., and Shirasu, Y. (1991). Fundam. Appl. Toxicol. 16, 667–686. Groups of 64 male and 64 female Wistar rats were given thiram at constant dietary doses of 0, 3, 30, and 300 ppm (0, 0.1, 1.2, and 11.6 mg/kg/day for males and 0, 0.1, 1.4, and 13.8 mg/kg/day for females) for 104 weeks. Eight males and eight females in each group were killed after Weeks 13, 26, and 52. For the dog study, four male and four female beagle dogs were allotted to each group and treated with the compound at 0, 0.4, 4, and 40 mg/kg/day for 104 weeks. The dogs in the 40 mg/kg/day group had severe toxic signs, including nausea or vomiting, salivation, and occasional clonic convulsion, and all were subjected to unscheduled necropsy before Day 203 of treatment. The dogs also had ophthalmological changes such as fundal hemorrhage, miosis, and desquamation of the retina which were consistent with the retinal lesions shown by histopathology. The rats of the high-dose group had retarded growth with a slightly decreased food intake. Anemia was evident in high-dose female rats and in middle- and high-dose dogs. Liver failure in male and female dogs and kidney damage in female dogs were detected in middle- and high-dose groups by blood biochemistry and/or histopathology. Regressive changes of the sciatic nerve accompanied by atrophy of the calf muscle were seen in female rats of the high-dose group but not in male rats. In high-dose rats, progression of myocardial lesions of the heart and chronic nephrosis of the kidney were depressed in males and females, respectively. Female rats of the middle- and high-dose groups had decreased occurrences of mammary fibroadenoma and decreased development of skin masses.

Antigenic Profile of Mammary Fibroadenoma and Cystosarcoma Phyllodes: A Study Using Antibodies to Estrogen- and Progesterone Receptors and to a Panel of Cell Surface Molecules

Using serial frozen sections, monoclonal antibodies and an indirect immunoperoxidase method, 13 fibroadenomas (FA) and 3 cystosarcomas phyllodes (CSP) were analyzed for the expression of Egp34, HEA319-antigen, leucocyte differentiation antigens CD10, CD30, CD57, CD72, CDw75, and CD77, epidermal growth factor receptor (EGFR), estrogen (ER) and progesterone receptor (PR), and transferrin receptor (CD71). Egp34, CDw75, HEA319 antigen, CD10, and CD30 turned out to be consistently expressed in different cell types constituting FA and CSP and revealed that in malignant CSP the myoepithelial compartment acquires the ability to invade the stroma. Phenomenologically, the variable mode of expression of CD57 in myoepithelial cells, of CD77 in ductal epithelium, and of CD72 in both epithelial and stromal cells is suggestive for reflecting differences in their functional state but cannot be further interpreted at present. Expression of PR and ER was restricted to duct cells and was relatively independent, non-systematical. However, expression of ER and EGFR was inverse. This was also true for EGFR and CD71 in both duct cells and myoepithelial cells of FA. In contrast, stromal cells of FA were able to co-express EGFR and CD71 in the absence of PR and ER. This suggests a hormone-independent stimulation of the stromal cell compartment, possibly leading to local proliferation as the primary event in tumorigenesis of FA. In malignant CSP, however, the main proliferating cell is an abnormally mobile, HEA319 antigen-, CD10- and CD30-positive myoepithelial cell found to co-express ERFR and CD71 which is abnormal for this cell type but encountered in (myo-)fibroblasts of FA.