Reversible fibroadenomatous mammary hyperplasia in male and female New Zealand white rabbits associated with cyclosporine A administration.

All male and female New Zealand white rabbits in a limbal cell graft study developed marked generalized mammary gland hypertrophy. Postprocedural medications included ophthalmic 0.1% dexamethasone, ophthalmic 0.5% cyclosporine, and subcutaneous cyclosporine A. Cytologic examination revealed epithelial clusters with minimal malignant criteria. On histologic evaluation, there was diffuse glandular hyperplasia with mild cellular atypia and ductal ectasia separated by abundant hypercellular fibrous stroma, consistent with fibroadenomatous mammary gland hyperplasia. The hyperplasia resolved within 2 weeks of cessation of cyclosporine, and at necropsy identifiable mammary masses were not found. Very little has been reported about the use of cyclosporine in laboratory rabbits and its association with development of mammary gland hyperplasia. This is the first report in which administration of cyclosporine to male and female rabbits at a dose as low as 5 mg/kg/day induced benign fibroadenomatous mammary gland hyperplasia. This change regressed after cessation of the drug.

Prenatal exposure to diethylstilbestrol: ovarian-independent growth of mammary tumors induced by 7,12-dimethylbenz[a]anthracene.

The effects of ovariectomy on the growth of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors were investigated after rats ahd been exposed prenatally to diethylstilbestrol (DES). Pregnant rats were inoculated with either DES (total dose: 1.2 micrograms) in sesame oil or with the vehicle alone on days 10 and 13 of gestation. Female offspring were given 2 gastric intubations of DMBA (10 mg each) 1 week apart beginning at 50 plus or minus 1 days of age. When the average diameter of a mammary tumor exceeded 2 cm, the animal was ovariectomized. The initial response of most tumors in both the DES-exposed and control groups to ovariectomy was size regression. The growth of 7 tumors that arose soon after DMBA treatment in each group was studied for 12-20 weeks after ovariectomy. Whereas only 1 tumor from the control group resumed active growth after the initial regression period, 6 tumors in the DES-exposed group overcame the initial effects of ovariectomy and began to grow again. Thus ovariectomy appeared to be less effective in producing sustained control growth in DMBA-induced mammary tumors in rats exposed prenatally to DES.

Inhibition of chemically induced mammary carcinogenesis in rats by short-term exposure to butylated hydroxytoluene (BHT): interrelationships among BHT concentration, carcinogen dose, and diet.

Dietary butylated hydroxytoluene (BHT) fed 14 days before and 14 days after carcinogen administration resulted in a dose-dependent inhibition of 7, 12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumor incidence in outbred Sprague-Dawley rats. In addition, the inhibitory effects of BHT were strongly influenced by the dose of initiating carcinogen and the type of diet in which BHT was administered. In animals fed the NIH-07 diet and receiving a low dose of DMBA (5 mg/rat), the inhibitory effect of BHT was manifested at all four BHT concentrations (6,000 leads to 300 ppm). Maximal inhibition was approximately 50% in animals given 5 mg DMBA and receiving 6,000 ppm BHT. However, in the group administered a high dose of DMBA (15 mg/rat), the inhibitory effect of BHT was expressed only at 6,000 ppm, the highest concentration given. Lower concentrations (300 and 1,000 ppm) of BHT had no detectable effect on tumor incidence. In animals fed the defined, semipurified AIN-76A diet during the 4-week treatment period and initiated with 5 mg DMBA, BHT at 6,000 ppm inhibited tumor development. However, at 15 mg DMBA animals fed the AIN-76A diet differed markedly from those fed the NIH-07 diet. In the former group, BHT at 6,000 ppm was unable to elicit any inhibitory response; in the latter group, BHT inhibited tumor development by 40%. Dietary BHT also inhibited DMBA-induced adrenocortical hyperplastic nodules in a dose-dependent fashion. These results indicate that short-term exposure to dietary BHT can inhibit experimental mammary tumor development at environmentally relevant concentrations.

Mammary tumor induction in male and female Sprague-Dawley rats by adriamycin and daunomycin.

Male and female noninbred Sprague-Dawley rats 30-36 days of age were given single iv injections of 10 or 5 mg adriamycin (Ad)/kg or 10 mg daunomycin (DM)/kg. Multiple mammary tumors (MT), mostly adenocarcinomas, were observed in 29 and 67% of the females given 10 and 5 mg Ad/kg, respectively, and in 64% of those given 10 mg DM/kg. The mean induction time for females receiving 10 mg Ad/kg was 135 days, for those receiving 5 mg/kg it was 114 days, and for those receiving DM it was only 80 days. Single MT, also mostly adenocarcinomas, were observed an average of 279 days from injection in 31% of the males given 5 mg Ad/kg and an average of 91 days from injection in 37% of the males given 10 mg DM/kg. No tumors were observed in the males given 10 mg Ad/kg, but these survived for only 79 days after treatment.

Assessment of interaction among three carcinogens on rat mammary carcinogenesis in a factorially designed experiment.

Female Sprague-Dawley rats were given by stomach tube 7,12-dimethylbenz[a]anthracene [(DMBA) CAS: 57-97-6] on the 77th day of age at the rate of 1.6 mg/100 g body weight, or procarbazine [(PCZ) CAS: 671-16-9] on the 84th day of age at the rate of 10 mg/100 g body weight, or 0.5 Gy of total-body x-rays on the 91st day of age, singly or in all possible combinations or no treatment. All rats were studied for mammary carcinogenesis for 370 days after the 84th day of age. Three measures of mammary carcinogenesis were studied. These were the incidence of rats with mammary adenocarcinomas, or mammary fibroadenomas, or mammary neoplasia of either type. Each of these measures was studied also for rats with 2 or more or 3 or more mammary neoplasms. Assessment of possible interaction among the three carcinogens with regard to the incidence of neoplasms was done by time-independent or time-dependent methods, both of which gave remarkably consistent results. For rats with 1 or more adenocarcinomas, 1 or more fibroadenomas, or 1 or more adenocarcinomas and/or fibroadenomas, both methods showed no interaction among the carcinogens, which can, therefore, be considered to have produced additive effects. An exception to this finding of additivity was an apparent synergistic interaction between DMBA and PCZ when the measures of rats with 2 or more, or 3 or more mammary neoplasms of either type, or 3 or more fibroadenomas were analyzed; these analyses, however, were based on relatively small numbers of rats with multiple tumors. Since no interactions were found for the usual measure of carcinogenesis, namely, incidence of rats with 1 or more neoplasms, the overall conclusion is that DMBA, PCZ, and x-ray act additively in the induction of mammary neoplasms in the female Sprague-Dawley rat.

Estrogen replacement therapy and benign breast disease.

The relationship between estrogen replacement therapy (ERT) and the risk of benign breast disease (BBD) was examined among 929 postmenopausal cases and 846 postmenopausal controls identified through a large breast cancer screening program. Prior use of ERT among postmenopausal women was associated with an increased risk of both fibrocystic breast disease [odds ratio (OR) = 1.4; 95% confidence interval (Cl) = 1.1-1.8] and fibroadenoma (OR = 1.6; Cl = 0.8-3.5). The risk of all BBD rose with increasing years of use (OR = 1.9 for greater than or equal to 15 yr of total use) and with years since initial use (OR = 1.6 for greater than or equal to 15 yr since first use). Among users of the conjugated estrogen Premarin, increased risks were found at all but the lowest dose. Finally, risks associated with ERT were higher in women with a bilateral oophorectomy than in other postmenopausal women. These results suggested, overall, an increased risk of BBD associated with ERT.

Induction of mammary neoplasms in the ACI rat by 430-keV neutrons, X-rays, and diethylstilbestrol.

Mammary tumorigenesis was studied in female ACi rats after treatment with X-irradiation or neutron-irradiation, with or without diethylstilbestrol (DES) treatment. The mortality-corrected cumulative tumor rate based on all mammary neoplasms and the mortality-corrected incidence based on the first neoplasms only have been derived. In non-DES-treated animals, at the relatively high radiation doses studied, all dose-effect relationships were consistent with relative biological effectiveness (RBE) values slightly in excess of 10. In DES-treated rats definite findings were observed at neutron doses as low as 0.01 Gy (1 rad). The dose-effect relationship in DES-treated rats showed a strong sublinearly (dose exponent less than 1) at low neutron doses. RBE values in DES-treated rats increased in inverse proportion to the square root of the neutron dose, and exceeded 100 at a neutron dose of 0.01 Gy (1 rad).

Comparative carcinogenicity of 5-nitrothiophenes and 5-nitrofurans in rats.

We investigated the carcinogenicity of five 5-nitrothiophenes with heterocyclic substituents at the 2-position of the thiophene ring by feeding the chemicals to Sprague-Dawley rats and comparing the type and incidence of lesions with those appearing after exposure to two 5-nitrofurans. Benign and malignant mammary tumors and intestinal tract sarcomas were the most frequent lesions induced by 5-nitrothiophenes. 4-Bis(2-hydroxyethyl)amino-2-(5-nitro-2-thienyl)quinazoline caused a 100% incidence of mammary adenocarcinomas in 28 female rats at risk; it induced 3 benign and 5 malignant mammary tumors and 13 small intestine sarcomas in 20 male rats. A high incidence of similar lesions was observed in male and female rats fed the corresponding 5-nitrofuran analogue, 4-bis(2-hydroxyethyl)amino-2-(5-nitro-2-furyl)quinazoline. In marked contrast, 4 of 28 female rats receiving 4-bis(2-hydroxyethyl)amino-2-(2-thienyl)quinazoline, which lacks the nitro group at the 5-position on the thiophene ring, had solitary benign mammary tumors (P greater than 0.2). Additional 5-nitrothiophenes demonstrating significant oncogenic activity for female rats were 4-morpholino-2-(5-nitro-2-thienyl)quinazoline, 4-(2-hydroxyethylamino)-2-(5-nitro-2-thienyl)quinazoline 4-(2,3-dihydroxypropylamino)-2-(5-nitro-2-thienyl)quinazoline, and 1,2-dihydro-2-(5-nitro-2-thienyl)quinazolin-4(3H)-one. Another nitrofuran, 4,6-dimethyl-2-(5-nitro-2-furyl)-pyrimidine, provided the following types of neoplasms in 30 female rats at risk: squamous cell carcinomas of the forestomach (30), sarcomas of the intestine (21), adenocarcinomas of the kidney (2).

Effects of exposure of neonatal mice to 17beta-estradiol on subsequent age-incidence and morphology of carcinogen-induced mammary dysplasia.

Mice exposed to estrogens as neonates developed more mammary dysplasias and had different morphologic types of dysplasias than did normal animals when both groups were exposed to a carcinogen: 1) before puberty, 2) during active mammary growth, 3) or at 6 months of age (the time when spontaneous dysplasias begin to appear in normal animals). The relative percentages of various morphologic types of dysplasias differed in hosts that received different treatments. The significance for subsequent patterns of mammary disease caused by exposure of neonates to 17beta-estradiol was discussed.

Proliferation of ductal outgrowths by carcinogen-induced rat mammary tumors in gland-free mammary fat pads.

The purpose of this study was to evaluate the gland-free mammary fat pad as a preferential site for transplantation of 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumors, since previous studies indicated their frequent failure to grow when transplanted in ectopic sites. Accordingly, samples from 14 primary mammary tumors (9 randomly selected and 5 ovarian-independent) were transplanted into the inguinal pairs of gland-free mammary fat pads of syngeneic female Lewis rats (9-12 wk of age). Although the percentage of takes was high (88%), the growth and morphogenetic capabilities of the transplants were strikingly different. Whereas transplants of ovarian-independent tumors consistently developed palpable carcinomas, transplants of all but 1 of the tumors selected at random (most of which were presumably ovarian-dependent) gave rise mainly to apparently normal ductal and hyperplastic outgrowths. The growth behavior of the transplants could not be correlated with the presence or absence in the tumors of mononuclear cells of the immune system. Unless the mammary fat pad selected against the growth of tumor cells, it seemed that the main alternative to tumor formation by the transplants was the proliferation of nontumorous outgrowths. These results draw attention to differences in the phenotypic stability of primary mammary tumors induced by DMBA and open up for further study the question of whether these differences reflect their cellular heterogeneity or their potential to undergo differentiation.

Carcinogenicity of the antineoplastic agent, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, and its metabolites in rats.

Chronic oral administration of the antineoplastic agent, 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (NSC-45388, DTIC), induced predominantly thymic and mammary tumors as demonstrated previously. Male and female Sprague-Dawley and female Buffalo rats were susceptible to the carcinogenicity of DTIC. A 50% incidence of mammary adenocarcinomas was induced in males within 18 weeks. Type of tumor and tumor incidence were dose dependent. Single and multiple intraperitoneal injections of DTIC did not alter organ specificity. DTIC-induced thymic lymphosarcomas and mammary adenocarcinomas were transplantable. Tissue distribution studies revealed no correlation between uptake of DTIC by a given tissue and its susceptibility to carcinogenicity. Metabolites of DTIC were tested for carcinogenic activity. Animals administered 5-diazoimidazole-4-carboxamide orally, intraperitoneally, or intragastrically developed low incidences of thymic, stomach, bladder, or mammary tumors. A low incidence of mammary tumors developed in rats fed 2-azahypoxanthine. A variety of tumors, including several ependymoblastomas, were induced in rats that received 5-aminoimidazole-4-carboxamide orally. 5-(3-Methyl-1-triazeno)imidazole-4-carboxamide (MTIC), when fed or given in single or multiple intraperitoneal injections, induced a high incidence of mammary adenofibromas and a low incidence of uterine leiomyosarcomas. Control rats had low incidences of mammary adenocarcinomas and adenofibromas after 52 weeks. These data show that the carcinogenic properties of DTIC resemble those of carcinogenic N-nitroso compounds, hydrazine, azo, and azoxy-alkanes and aryltriazenes and thus suggest similar mechanism(s) of action. These data also indicate that MTIC is involved in the induction of mammary adenofibromas and uterine leiomyosarcomas by DTIC.

Irradiation and prolactin effects on rat mammary carcinogenesis: intrasplenic pituitary and estrone capsule implants.

The implantation of silicone capsules that contained estrone and that were adjacent to grafts of anterior pituitary tissue in the spleens of adrenalectomized glucocorticoid-deficient inbred F344 rats resulted in high circulating prolactin (Prl) levels without the untoward effects of chronic hyperestrogenism or of grafts of Prl-secreting pituitary tumors. All peripheral serum estrone titers were below the titers in sera of proestrous untreated intact rats. Peripheral serum estrone and Prl levels were, however, a function of capsule surface area over the capsule sizes tested (12-74 mm2); the elevated Prl levels persisted for as long as 700 days. In adrenalectomized glucocorticoid-deficient female rats, both 5 Gy gamma-irradiation alone and intrasplenic pituitary-estrone implants alone induced mammary carcinomas; the combination of these treatments induced a greater incidence of first carcinomas and reduced first carcinoma latency. There were, however, no marked differences in tumor incidence or latency due to differences in estrone capsule size. Finally, ovariectomy reduced first carcinoma risk in irradiated, pituitary-estrone-implanted rats but did not change the time of maximum risk. Ovarian secretory activity thus persisted in such rats and ovarian hormones synergized with Prl in mammary carcinoma induction.

Inhibitory effect of disulfiram on rat mammary tumor induction by N-2-fluorenylacetamide and on its metabolic conversion to N-hydroxy-N-2-fluorenylacetamide.

The effect of an antioxidant, disulfiram (DSF), on the carcinogenicities of N-2-fluorenylacetamide (2-FAA) and N-hydroxy-N-2-fluorenylacetamide (N-OH-2-FAA) was examined. DSF given in a diet at a concentration of 0.9% for 1 week before and throughout the carcinogen treatment (0.1 mmol/kg 3 times a week for 4 weeks) reduced the incidence of mammary tumors induced with 2-FAA by 50% and extended the mean latency period of malignant tumors from 5 to 10 months. By contrast, DSF had no effect on mammary carcinogenesis by N-OH-2-FAA. Consistent with these results was the demonstration of the inhibitory effect of DSF on the first step of metabolic activation of 2-FAA, i.e., N-hydroxylation. N-hydroxylation of 2-FAA was significantly inhibited in hepatic microsomes of untreated and 2-FAA-treated male and female rats by DSF given orally. A similar inhibition was shown in vitro after preincubation of hepatic microsomes with DSF. Measurements of cytochrome P450 after pretreatment of rats or microsomes with the inhibition showed no appreciable changes in the hemoprotein content. It was concluded, therefore, that the inhibitory effect of DSF on N-hydroxylation of 2-FAA is accomplished through mechanism(s) other than depression of the cytochrome P450 level. Because both 2-FAA and DSF bind to cytochrome P450 producing a type I spectrum, DSF may interfere with the binding of 2-FAA and thus alter its metabolism.

Uterine adenofibroma and endometrial stromal sarcoma associated with tamoxifen therapy: MR findings.

Tamoxifen therapy may result in a variety of endometrial proliferative lesions, including adenofibroma and endometrial stromal sarcoma (ESS). This report describes the MR findings of adenofibroma and ESS associated with tamoxifen therapy. When MRI demonstrates a uterine mass appearing as a heterogeneous mass in the endometrium or myometrium, adenofibroma and ECC must be considered as rare, but possible, diagnoses.

Mammary tumors induced in rats by adriamycin and daunomycin.

The two anthracycline antitumor antibiotics, Adriamycin and daunomycin (DM), induced a high incidence of mammary tumors, both fibroadenomas and adenocarcinomas, in female rats that received a single i.v. dose, thus confirming previous results. The incidence of DM-induced adenocarcinomas increased with the dose of the drug, whereas the incidence of Adriamycin-induced adenocarcinomas showed a plateau at 5 mg/kg and above. Adriamycin- and DM-induced fibroadenomas showed a peak at lower doses (about 5 to 6 mg/kg). With the highest DM dose (12.5 mg/kg) used, there was a slight prevalence of adenocarcinomas over fibroadenomas.

Comparative carcinogenicities of 1-, 2-, and 4-nitropyrene and structurally related compounds in the female CD rat.

The comparative carcinogenicities of N-hydroxy-N-acetyl-1-aminopyrene, N-acetyl-1-aminopyrene, and 1-, 2-, and 4-nitropyrene were determined following i.p. injection into weaning female CD rats (67 mumol/kg body weight in dimethyl sulfoxide; 3 times/week for 4 weeks). At sacrifice 61 weeks after the first injection the incidences of malignant mammary tumors were increased significantly to 45 and 24% in the 4-nitropyrene- and N-hydroxy-N-acetyl-2-aminofluorene-treated groups, respectively. Cellular altered foci in the liver were increased significantly in the N-acetyl-1-aminopyrene-, N-hydroxy-N-acetyl-1-aminopyrene-, and N-hydroxy-N-acetyl-2-aminofluorene- treated groups; the latter two compounds also led to significantly increased formation of hyperplastic nodules in this organ. Significant increases in leukemia induction were observed in animals treated with 2-nitropyrene or N-hydroxy-N-acetyl-2-aminofluorene. In an experiment designed to compare the influence of the route of administration on the carcinogenic potential of this agent, 1-nitropyrene was injected i.p. or s.c. into weanling female CD rats (100 mumol/kg body weight; once a week for 4 weeks). The animals were sacrificed at 87 to 90 weeks after the first treatment. The incidences of mammary gland tumors in animals receiving injections of 1-nitropyrene by either route (59%) were significantly higher than in solvent-injected controls (37%). The incidences of adenocarcinoma in the i.p. 1-nitropyrene group (28%) and fibroadenoma in the s.c. 1-nitropyrene group (52%) were significantly higher than in the control animals (7 and 27%, respectively). These data suggest that the demonstration of the weak carcinogenicity of 1-nitropyrene is probably more a function of the length of the observation period than of the routes of administration used here. A further exploration of the effect of the route of administration involved treatment of weanling female CD rats by direct injection of 1-, 2-, or 4-nitropyrene into the mammary fat pads. A total of 2.04 mumol of the nitrocompound in dimethyl sulfoxide was injected into the mammary glands under each of the 6 left nipples. The right mammary glands were treated with the solvent only. Injections of the thoracic nipple areas were carried out on day 1; inguinal areas were treated on day 2. The animals were sacrificed after 77 weeks. The number of mammary tumor-bearing animals (23 of 28), the number with fibroadenoma (15 of 28), and the number with adenocarcinoma (19 of 28) were significantly increased in the 4-nitropyrene-treated group as compared with animals treated with only dimethyl sulfoxide.(ABSTRACT TRUNCATED AT 400 WORDS)

Influence of dietary medium-chain triglycerides on the development of N-methylnitrosourea-induced rat mammary tumors.

The mammary tumor-promoting effects of a high-fat (HF) diet (23%, w/w) containing a 3:1 mixture of medium-chain triglycerides (MCT) and corn oil were compared with those of a low-fat (LF) corn oil diet (5%) and a HF: corn oil diet (23%, w/w). It was found that the ingestion of MCT in a HF diet resulted in no detectable tumor-promoting effects in animals initiated with the potent mammary carcinogen N-nitrosomethylurea. Total palpable mammary tumor incidence was 60% in the HF:corn oil plus MCT group, 66% in the LF:corn oil group, and 87% in the HF:corn oil group (p less than 0.03 and p less than 0.06, respectively). However, when palpable adenocarcinomas only were counted, differences in incidence between groups were not statistically significant, HF:MCT (57%) versus HF:corn oil (77%), p less than 0.08. Mean time to first tumor (days) was 122 +/- 40 (S.D.) in the MCT, 117 +/- 36 in the LF:corn oil groups, and 86 +/- 23 in the HF:corn oil group. The cumulative tumor incidence curves were similar for the MCT and LF:corn oil groups (p less than 0.9); however, both curves were significantly different from that of the HF:corn oil group (p less than 0.0099). No differences were found in tumor multiplicity, tumor size, or body weight gain in any of the treatment groups. Assay of serum total cholesterol and triglycerides showed that consumption of 23% corn oil diet significantly depressed serum cholesterol (but not triglyceride) levels compared to the LF:5% corn oil- and the HF:MCT-containing diets. Analysis of serum fatty acid profiles indicated that animals fed 23% corn oil exhibited twice the amount of linoleic acid (C18:2) as did those fed either 5% corn oil or MCT. Differences in other fatty acids were of a much lesser magnitude. These results indicate that the mammary tumor-promoting effect of a HF diet can be diminished by substituting saturated MCT for the more common longer-unsaturated-chain triglycerides. In addition, they suggest an association between promotion of mammary cancer and elevated levels of linoleic acid in serum lipids.

Enhanced development of mammary tumors in rats following transplacental and neonatal exposure to ethylnitrosourea.

Transplacental and neonatal induction of mammary tumors (MT's) with ethylnitrosourea (ENU) was studied in Sprague-Dawley rats. A low transplacental ENU dose (10 mg/kg) did not increase the number of MT's or shorten their latency period. High ENU doses (30 mg/kg neonatal, 60 mg/kg transplacental, or 120 mg/kg transplacental) when corrected for differences in life span caused a significant shortening of the tumor induction period and an overall increase in the tumor incidence. With high ENU doses, the MT's were frequently multiple in the same animal and were more often malignant. Tumors developed mostly in females; only a few were observed in males. It is concluded that with a sufficient dose of the carcinogen in susceptible animals, transplacental and neonatal ENU mammary carcinogenesis takes place. The experiment was originally designed to evaluate ENU-induced neurogenic tumors; the results on MT's were obtained incidentally.

Apparent rat strain-related sensitivity to phorbol promotion of mammary carcinogenesis.

It has been reported that twice-weekly i.p. injections of 4 mg phorbol for 10 weeks, after a single feeding of 6 mg dimethylbenz(a)anthracene (DMBA) in female Wistar rats, led to a significant augmentation of mammary adenocarcinoma incidence and of lymphatic leukemia incidence as compared to 6 mg DMBA alone. In an experiment reported here, in female Sprague-Dawley rats, using the same doses of DMBA and phorbol and the same injection schedule, phorbol given after DMBA did not augment mammary adenocarcinoma incidence or lymphatic leukemia incidence as compared to DMBA given alone. It thus appears that there is a strain-related sensitivity between Wistar and Sprague-Dawley rats with regard to the promoting activity of phorbol when phorbol treatment follows DMBA treatment, and mammary adenocarcinoma incidence and lymphatic leukemia incidence are studied. Further, in Sprague-Dawley rats, phorbol did not promote mammary fibroadenoma incidence in DMBA-treated rats, mammary adenocarcinoma incidence in procarbazine-treated rats, and mammary adenocarcinoma incidence or mammary fibroadenoma incidence in X-ray-treated rats. DMBA and procarbazine, with or without phorbol, tended to induce more mammary neoplasms in the anterior (thoracic) than in the posterior (abdominal) mammary glands. X-irradiation tended to induce mammary neoplasms in approximately equal numbers in the anterior and posterior mammary glands. It was suggested that regional differences in chemically induced mammary carcinogenesis were due to a difference in the transport and delivery of the chemical carcinogens to the regions rather than a difference in the amount of mammary gland tissue in the regions. An analysis of the numbers of Sprague-Dawley rats that developed either no mammary neoplasms, or only mammary adenocarcinomas, or only mammary fibroadenomas, or both mammary adenocarcinomas and mammary fibroadenomas in response to DMBA, procarbazine, and X-ray, suggested that the development of a mammary adenocarcinoma or the development of a mammary fibroadenoma are independent processes.

Inhibition of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis by retinyl acetate.

The administration of 2.5 mg retinyl acetate daily in the diet to female Sprague-Dawley rats beginning 7 days after the intragastric instillation of either 2.5, 5, or 15 mg 7,12-dimethylbenz(a)anthracene (CMBA) resulted in a reduction in the incidence of benign mammary tumors of 37, 30, and 31%, respectively. An equally significant reduction in the number of tumors was also evident. Although no difference was noted in the percentage incidence of mammary adenocarcinomas between the placebo and 2.5 mg retinyl acetate-treated groups at the 2.5-mg DMBA level, the percentage incidence was reduced by 52 and 39% in these groups at the 5- and 15-mg DMBA dose. Furthermore, the number of adenocarcinomas was also significantly reduced. Although both the percentage incidence and number of tumors were reduced by treatment with 1 mg retinyl acetate, these differences were not statistically significant. Liver histology and liver function tests of rats of the retinyl acetate groups did not differ from that of the control group. Similarly, the estrus cycle of treated animals did not differ from that of control rats. These data indicate that relatively large doses of retinyl acetate significantly inhibit the development of DMBA-induced mammary adenocarcinomas and benign tumors. Furthermore, the suppression of mammary tumorigenesis is apparently not the result of an alteration in either the metabolism of DMBA or estrogen nor to an inhibition of tumor growth resulting from retinyl acetate toxicity. The inhibitory effect of retinyl acetate may be related to the effect of retinoids on epithelial cell differentiation and/or reversal of carcinogen-induced anaplasia.