Pathology Working Group review and evaluation of proliferative lesions of mammary gland tissues in female rats fed ammonium perfluorooctanoate (APFO) in the diet for 2 years.

Perfluorooctanoate (PFO) is a perfluorinated carboxylate that is widely distributed in the environment. A 2-year chronic study was conducted in rats fed either 30 or 300 ppm of ammonium perfluorooctanoate (APFO). To investigate the possible relationship of APFO exposure to proliferative mammary lesions, a Pathology Working Group (PWG) review of the original slides was performed. The consensus reached by the PWG was that the incidence of mammary-gland neoplasms was not affected by chronic dietary administration of APFO. Therefore, feeding female rats up to 300 ppm of APFO resulted in no increase in proliferative lesions of the mammary tissue.

Effect of Converting From Calcineurin Inhibitor- to Sirolimus-Based Immunosuppressant Regimen on Breast Fibroadenoma Among Kidney Transplant Patients.

The incidence rate of breast fibroadenomas is higher among female kidney transplant (KT) patients treated using cyclosporine (CsA) for immunosuppression than in the general population. As such, there is an effort to convert immunosuppression from CsA or tacrolimus to sirolimus. Our aim was to assess the reversibility of a breast fibroadenoma after conversion in a small cohort of female KT recipients. This was an open-label, single-arm study including 128 female KT recipients, with a positive finding of a breast fibroadenoma in 15. Lesions were classified according to the Breast Imaging Reporting and Data System (BIRADS). Among these 15, a total of 7 converted from tacrolimus to sirolimus and 8 converted from CsA. We measured the change in BIRADS category and hormone and cytokine levels from baseline to 12 months after conversion. The primary outcome was progression or reversal of existing fibroadenomas at 12 months after conversion. Secondary outcomes were differences in hormone and cytokine levels. Conversion from CsA or tacrolimus to sirolimus had no significant effect on the BIRADS classification. However, conversion to sirolimus did produce a significant decrease in the level of transforming growth factor ß cytokine, this level being closely associated with fibroadenomas. Conversion from a calcineurin inhibitor to sirolimus can block the progression of fibroadenomas. Further research is needed to confirm our results.

Carcinogenic effects of intragastric 3-methylcholanthrene and 7,12-dimethylbenz[a]anthracene in Wistar and Sprague-Dawley rats.

In 2 experiments involving 384 rats of the Wistar (W) and Sprague-Dawley (SD) strains, the carcinogenic effects of repeated intragastric instillations of 3-methylcholanthrene (MCA) were compared with those of single intragastric doses of 7,12-dimethylbenz[a]anthracene (DMBA). Mammary carcinomas appeared in a higher proportion and earlier in SD than in W rats exposed to either carcinogen (during 36 weeks, 90 vs. 50% with MCA in SD and W rats, at an average of 12 and 15 weeks, respectively, and 80 vs. 64% with DMBA in SD and W rats, at an average of 16 and 22 weeks, respectively). Fibroadenomas of the breast were seen in 20 percent of SD rats by 36 weeks. In W rats observed for 1 year following DMBA administration, Fibroadenomas occurred in 64 percent and adenosis in 49 percent, at an average of 45 to 51 weeks, whereas after MCA administration these reactions occurred in less than 10 percent. Intraluminal secretion indicative of lactation was noted in approximately 20 percent of fibroadenomas and adenoses. Nine W rats developed lymphoma, 5 following DMBA and 4 following MCA administration. Uterine papillary formations were observed in 1 W and 2 SD rats, and uterine carcinomas in 2 SD rats; 3 animals had received DMBA and 2, MCA.

Potent mammary carcinogenicity in female CD rats of a fjord region diol-epoxide of benzo[c]phenanthrene compared to a bay region diol-epoxide of benzo[a]pyrene.

Two diol-epoxide metabolites of benzo[c]phenanthrene and benzo[a]pyrene, polynuclear aromatic hydrocarbons which occur in the environment, were tested for carcinogenicity by direct injection into the mammary fat pads of female CD rats. The compounds anti-3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene (BcPDE), a fjord region diol-epoxide, and anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, a bay region diol-epoxide, were applied at total doses of 12.2 mumol. 6-Nitrochrysene was applied at the same dose as a positive control (K. El-Bayoumy, A. Rivenson, P. Upadhyaya, Y-H. Chae, and S. S. Hecht, Cancer Res. 53: 3719-3722, 1993). The sterically hindered fjord region diol-epoxide BcPDE was a powerful mammary tumorigen and carcinogen, rapidly inducing significantly more fibroadenoma and adenocarcinoma than either of the other compounds. Anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene was a weaker mammary tumorigen than BcPDE and 6-nitrochrysene. The results of this study provide the first evidence for mammary tumorigenicity of polynuclear aromatic hydrocarbon diol-epoxides and demonstrate the potent mammary carcinogenicity of BcPDE.

Exposure of Sprague-Dawley rats to a 50-Hertz, 100-microTesla magnetic field for 27 weeks facilitates mammary tumorigenesis in the 7,12-dimethylbenz[a]-anthracene model of breast cancer.

We have shown previously (W. Löscher et al., Cancer Lett., 71: 75-81, 1993; M. Mevissen et al., Carcinogenesis (Lond.), 17: 903-910, 1996) that 50-Hz magnetic fields (MFs) of low [50 or 100 microTesla (T)] flux density enhance mammary gland tumor development and growth in the 7,12-dimethylbenz[a]anthracene (DMBA) model of breast cancer in female Sprague Dawley rats. In these previous experiments, groups of rats were given 20 mg of DMBA (four weekly gavage doses of 5 mg each) and were MF- or sham-exposed for 13 weeks. The objective of the present study was to examine whether the use of a lower dose of DMBA (10 instead of 20 mg per rat), MF exposure of the rats before DMBA injection, and the increase of the MF exposure period after DMBA application to 26 weeks enhance the effect of MF on tumor development and growth. A group 99 rats was exposed to a homogeneous, horizontally polarized 100-microT MF of 50-Hz for 24 h/day for 7 days/week; another group of 99 rats was sham-exposed under the same environmental conditions as the MF-exposed rats. The exposure chambers were identical for MF-exposed and sham-exposed animals. The age of the rats was 45-49 days at the onset of exposure; duration of MF or sham exposure was 27 weeks. DMBA was administered p.o. at a dose of 10 mg/rat after 1 week of MF or sham exposure. The animals were palpated once weekly from week 6 onwards to assess the development of mammary tumors. At the end of the exposure period, the animals were killed for the determination of number and volume and histological verification of mammary tumors. All of the recordings were done in a blinded fashion; i.e., the investigators were not aware which animals were MF- or sham-exposed. Mammary tumor development and growth was significantly enhanced by MF exposure, the most marked effect on tumor incidence (190% above sham control) being observed 13 weeks after DMBA administration. At the time of necropsy, i.e., 26 weeks after DMBA administration, the incidence of histologically verified mammary tumors was 50.5% in controls and 64.7% in MF-exposed rats, the difference being statistically significant. More marked intergroup differences were recorded when tumor incidence was separately evaluated for each of the six mammary complexes, the most pronounced MF effect on tumor incidence being seen in the cranial thoracic complex. The data substantiate that, at least under the experimental conditions used in our laboratory, 50-Hz, 100-microT MF exposure significantly facilitates the development and growth of mammary tumors in the DMBA rat model of breast cancer.

Development of early malignant bilateral breast disease in relation to antidepressant treatment.

The aim of this study is to present two rare cases of young female patients who were under antidepressant medication and developed bilateral breast disease; histology confirmed the noninvasive, malignant nature. The role of that type of agents in the breast pathology is briefly discussed, based on the data of the current literature.

Effects of arctiin on PhIP-induced mammary, colon and pancreatic carcinogenesis in female Sprague-Dawley rats and MeIQx-induced hepatocarcinogenesis in male F344 rats.

Chemopreventive effects of arctiin, a lignan isolated from Arctium lappa (burdock) seeds, on the initiation or post initiation period of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induced mammary carcinogenesis in female rats and on 2-amino-3, 8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)-associated hepatocarcinogenesis in male rats were examined. In experiment 1, female Sprague-Dawley (SD) rats were given intragastric doses of 100 mg/kg body wt of PhIP once a week for 8 weeks as initiation. Groups of 20 rats each were treated with 0.2 or 0.02% arctiin during or after PhIP initiation. Control rats were fed 0.2 or 0.02% arctiin, or basal diet alone during the experimental period. Animals were killed at the end of week 48. Although the incidence of mammary carcinomas did not significantly differ among the PhIP-treated groups, multiplicity was significantly decreased in rats given 0.2 (0.7+/-0.7, P<0.05) or 0.02% (1.0+/-1.1, P<0.05) arctiin after PhIP initiation as compared with the PhIP alone controls (2.1+/-2.5). The average number of colon aberrant crypt foci was also significantly decreased in these two groups. Pancreas acidophilic foci were induced in PhIP treated animals with slight decrease in the multiplicity with arctiin during the initiation phase. For liver carcinogenesis, groups of 15 male F344 rats were given a single intraperitoneal injection of diethylnitrosamine (DEN) and starting 2 weeks later, they were administered 0.03% MeIQx in the diet, MeIQx together with 0.5% arctiin, 0.1% arctiin or basal diet for 6 weeks. They were subjected to two-third partial hepatectomy 3 weeks after DEN initiation and killed at the end of week 8 for glutathione S-transferase placental form (GST-P) immunohistochemistry. The numbers and areas of preneoplastic GST-P positive foci were elevated by the treatment with MeIQx, and further increased by the simultaneous treatment with arctiin. These results indicate that arctiin has a protective effect on PhIP-induced carcinogenesis particularly in the mammary gland in the promotion period. On the other hand, it may have a weak co-carcinogenic influence on MeIQx-induced hepatocarcinogenesis. In addition, the results suggested that PhIP is a weak pancreatic carcinogen in female SD rats, targeting acinar cells.

Inhibitory potential of pregnancy and lactation on mammary carcinogenesis induced by a food-derived carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, in Sprague-Dawley rats.

Effects of pregnancy and lactation on a food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary carcinogenesis were investigated in female Sprague-Dawley rats. When rats were administrated PhIP in the diet (100 ppm) for 15 weeks, palpable subcutaneous tumors were first detected at week 24 in three nulliparous rats, while tumor latency was apparently increased in animals undergoing delivery and weaning during the PhIP administration period. However, since the incidence of palpable tumors was not consistently increased in the nulliparous animals, possibly due to the short PhIP-treatment, and the fact that spontaneous tumors developed in parous animals after week 44, the final incidences and multiplicities of histopathologically confirmed adenocarcinomas at week 48 were not significantly different between the two groups. These findings art partly supported by the epidemiological evidence that breast cancer is more prevalent in nulliparous than in parous women.

Magnetic fields and mammary cancer in rodents: a critical review and evaluation of published literature.

Epidemiological data suggesting a possible increase in breast cancer risk in male electricians have raised concerns about the relationship between exposure to power-frequency magnetic fields and breast cancer. In this paper, we review the results of animal studies that are relevant to identifying possible increases in breast cancer risk resulting from exposure to 50 or 60 Hz magnetic fields. Three large-scale chronic bioassays of carcinogenesis in rats or mice exposed to magnetic fields for 2 years demonstrated no increases in the incidence of mammary cancer; it is generally accepted that power-frequency magnetic fields have little or no activity as a complete carcinogen in the rodent mammary gland. Findings from one laboratory, though inconsistent, suggest that magnetic fields may stimulate mammary neoplasia in rats treated with a chemical carcinogen. However, studies conducted in two other laboratories failed to confirm these findings; rats exposed to magnetic fields demonstrated patterns of tumor incidence, multiplicity, size and latency that were generally similar to those in sham-exposed controls. Where differences were seen, the groups exposed to magnetic fields generally had fewer mammary tumors than did sham-exposed controls. On this basis, evaluations of the activity of 50 or 60 Hz magnetic fields in models of multistage mammary cancer in rodents have generally been negative; positive findings have been reported from only one laboratory. The totality of rodent data does not support the hypothesis that power-frequency magnetic-field exposure enhances mammary cancer in rodents, nor does it provide experimental support for possible epidemiological associations between magnetic-field exposure and increased breast cancer risk.

Experimental studies on the long-term effects of methylphenidate hydrochloride.

Toxicology and carcinogenesis studies of methylphenidate hydrochloride, a drug used in the treatment of attention-deficient disorders, were performed in F344 rats and B6C3F1 mice. In these studies, methylphenidate hydrochloride was administered for 2 years at doses of 0, 100, 500 or 1000 ppm in the feed to rats and at doses of 0, 50, 250, 500 ppm to mice in groups that consisted of 50 animals/dose/sex/species. The average amount of methylphenidate consumed per day was estimated to be 4-47 mg/kg/day for rats and 5-67 mg/kg/day for mice. Survival was similar in dosed and control groups. An increase in benign tumors of the liver and increased liver weights were observed in male and female mice at the high dose. An increase in hepatoblastomas was also seen in high dose male mice. Methylphenidate was not mutagenic in the Salmonella assay system, and it is hypothesized that this tumorigenic effect might be due to nongenotoxic effects of the chemical such as an increase in cell proliferation. Increased incidences of neoplasms were not seen in rats. However, there was a notable decrease in mammary gland fibroadenomas in female rats and a marginal decrease in benign pheochromocytomas in male rats. Epidemiology studies of methylphenidate have found no evidence of a carcinogenic effect in humans and like our findings in rats, report a less than expected rate of cancers in patients taking methylphenidate.

Long-term effects of inhaled nicotine.

Tobacco smoking has been reported to be associated with increased risk of cardiovascular disease and cancer, particularly of the lungs. In spite of extensive research on the health effects of tobacco smoking, the substances in tobacco smoke exerting these negative health effects are not completely known. Nicotine is the substance giving the subjective pleasure of smoking as well as inducing addiction. For the first time we report the effect on the rat of long-term (two years) inhalation of nicotine. The rats breathed in a chamber with nicotine at a concentration giving twice the plasma concentration found in heavy smokers. Nicotine was given for 20 h a day, five days a week during a two-year period. We could not find any increase in mortality, in atherosclerosis or frequency of tumors in these rats compared with controls. Particularly, there was no microscopic or macroscopic lung tumors nor any increase in pulmonary neuroendocrine cells. Throughout the study, however, the body weight of the nicotine exposed rats was reduced as compared with controls. In conclusion, our study does not indicate any harmful effect of nicotine when given in its pure form by inhalation.

Multiple bilateral fibroadenomas of the breasts requiring mastectomy in a renal transplant patient.

Fibroadenomas of the breast have been reported in female renal graft recipients and associated with the use of cyclosporin A (CsA). We report the case of a young patient given CsA who developed multiple bilateral fibroadenomas of the breasts 3 years after renal transplantation, leading to bilateral mastectomy. We discuss the association of CsA with fibroadenomas, the mechanisms by which the drug can act and review the literature. Based on these observations, an early conversion from CsA to tacrolimus should be considered; further observations are needed to assess the reversibility of the breast(s) lesions after such immunosuppressive regimen switch.

Breast fibroadenomas in renal transplant recipients.

Breast fibroadenomas are the most common solid lesions found in young women. We report on four patients who underwent renal transplantation and developed bilateral fibroadenomas while on cyclosporine (CsA). One patient developed symptomatic giant fibroadenomas and underwent bilateral mammoplasty. A significant decrease in the size of the breasts was noticed after switching to tacrolimus in three patients. Awareness of the association between CsA and fibroadenomas should help to achieve the correct diagnosis in transplant patients without subjecting them to unnecessary procedures.

Benign and malignant mammary tumors induced by DMBA in female Wistar rats.

This study pretends to characterize 7, 12-dimetylbenz[a]anthracene-induced benign and malignant tumors. One hundred and twenty female Wistar rats were randomly allocated to two groups: Control Group and Induction Group; IG animals were given a single dose of DMBA and killed 24 weeks after. Other tumors besides breast tumors were diagnosed, mainly tumors of the salivary glands and ovarian benign epithelial tumors. Incidence of breast disorders was about 60%. Macroscopic mammary tumors varied in dimension from 2 mm to 55 mm. Malignant breast tumors (n = 56) were essentially invasive ductal carcinomas (91.1%), G1 (92.2%), presenting histologic characteristics of good prognosis. Predominant benign breast disorders consisted of glandular (68.6%) and atypical (20%) hyperplasias reproducing histologic types of human breast diseases. Different individual susceptibility to DMBA apparently occurs; while some rats never developed neoplasias, others exhibited several tumors.

Comparison of the histological changes in the dog after treatment with the progestins medroxyprogesterone acetate and proligestone.

Administration of progestins in the dog may result in overproduction of growth hormone, suppression of the hypothalamic-pituitary-adrenocortical axis, and insulin resistance. In this paper we present a comparison of the histological findings in control dogs and dogs treated with either medroxyprogesterone acetate (MPA) or proligestone (PROL). Depot preparations of MPA or PROL were administered (SC) at 3-week intervals in two groups of seven ovariohysterectomized beagle dogs, after which three dogs of each group were killed. After a 6-month period without hormone treatment during which recovery was studied, the remaining dogs received five additional injections at the same interval and were subsequently killed. Tissue samples of four intact female beagle dogs served as controls. Progestin treatment resulted in atrophy of the adrenal cortex. In both MPA- and PROL-treated dogs, the thickness of the combined zona fasciculata and reticularis was significantly smaller than in control animals. In the mammary glands of progestin-treated dogs there were well developed alveoli and normal ducts adjacent to foci of hyperplastic ductular epithelium. Five dogs in each treatment group had developed benign mammary tumours which varied from simple tubular and papillary adenomas to benign complex and mixed tumours, whereas no mammary tumours were observed in the control animals. In each treatment group, steroid-induced hepatopathy was observed in the liver of three dogs. Vacuolation of the cells of the islets of Langerhans and the epithelium of the intercalated ducts was present in two dogs of each treatment group and was only observed after the second series of progestin administrations. Incidental findings included chronic pyelonephritis, aspecific dermatitis, and mucinous dysplasia of the gall bladder. No abnormalities were found in sections of spleen, lung, brain, or pituitary gland. There were no significant differences in the frequencies of the various abnormalities between MPA- and PROL-treated dogs. Our findings correspond with the clinical and biochemical results after treatment of dogs with MPA and PROL. The high incidence of mammary tumours might be associated with our recent finding that in the dog progestins induce ectopic production of growth hormone in the mammary gland. The dog might be a good model for further studies on hormonally induced breast cancers.

Mammary fibroadenomatous hyperplasia in a young cat attributed to treatment with megestrol acetate.

A male, neutered cat was presented for lethargy, reluctance to walk, and mammary enlargement after recent treatment with megestrol acetate. Mammary fibroadenomatous hyperplasia was diagnosed on the basis of history, clinical signs, and histopathological findings. Pathogenesis, clinical signs, and treatment options for mammary fibroadenomatous hyperplasia attributed to megestrol acetate treatment are discussed.

Atrazine and breast cancer: a framework assessment of the toxicological and epidemiological evidence.

The causal relationship between atrazine exposure and the occurrence of breast cancer in women was evaluated using the framework developed by Adami et al. (2011) wherein biological plausibility and epidemiological evidence were combined to conclude that a causal relationship between atrazine exposure and breast cancer is "unlikely". Carcinogenicity studies in female Sprague-Dawley (SD) but not Fischer-344 rats indicate that high doses of atrazine caused a decreased latency and an increased incidence of combined adenocarcinoma and fibroadenoma mammary tumors. There were no effects of atrazine on any other tumor type in male or female SD or Fischer-344 rats or in three strains of mice. Seven key events that precede tumor expression in female SD rats were identified. Atrazine induces mammary tumors in aging female SD rats by suppressing the luteinizing hormone surge, thereby supporting a state of persistent estrus and prolonged exposure to endogenous estrogen and prolactin. This endocrine mode of action has low biological plausibility for women because women who undergo reproductive senescence have low rather than elevated levels of estrogen and prolactin. Four alternative modes of action (genotoxicity, estrogenicity, upregulation of aromatase gene expression or delayed mammary gland development) were considered and none could account for the tumor response in SD rats. Epidemiological studies provide no support for a causal relationship between atrazine exposure and breast cancer. This conclusion is consistent with International Agency for Research on Cancer's classification of atrazine as "unclassifiable as to carcinogenicity" and the United States Environmental Protection Agency's classification of atrazine as "not likely to be carcinogenic."

Association between glycodelin and aryl hydrocarbon receptor in Iranian breast cancer patients: impact of environmental endocrine disrupting chemicals.

Breast cancer affects Iranian women one decade younger than their counterparts in other countries and the underlying risk factors have remained controversial. The aryl hydrocarbon receptor (AhR) mediates the effects of many environmental endocrine disruptors and contributes to the many other genes and Gd is an endocrine-regulated glycoprotein which may induce by AhR ligands in endometrium. This study has aimed to compare the interactions between Gd and AhR and other fundamental genes (p53, K-Ras, ER, PgR, AR) between pre and post menopausal Iranian breast cancer patients. To conduct immunohistochemical studies with appropriate monoclonal antibodies, 25 premenopausal invasive ductal carcinomas and 29 postmenopausal invasive ductal carcinomas were selected retrospectively in 2008-2010 from the pathology department of Imam Khomeini hospital complex of Tehran. Higher levels of AhR in epithelial cells of premenopausal patients and breast fibroadenoma emphasized the susceptibility of these cells to environmental induced tumors. Current study demonstrated a significant association between tumoral levels of Gd and AhR (p=0.002) in breast cancers which confirms the preliminary hypothesis about the role of TCDD exposure on Gd biosynthesis and secretion in TCDD-treated endometrial epithelial cells. In summary this study showed the dual prognostic role of Gd especially in premenopausal breast cancer which could be induced by AhR overexpression. Further studies are necessary to find the direct role of breast carcinogens as well as endocrine disrupting chemicals on the differential levels of Gd in breast tumors.