Induction Of Mammary Carcinomas Research Articles

Transcutaneous Electrical Stimulation, Interferential Current and Photobiomodulation May Lead to the Recurrence of Breast Cancer in Rats?

Introduction: Transcutaneous electrical nerve stimulation (TENS), interferential current therapy (IFC) and photobiomodulation therapy (PBMT) have been used in the management of cancer-related pain in adults. However, there are still some controversy regarding the effects of this therapy on tumor cells that may remain after cancer treatment. Objective: To evaluate the risk of recurrence of breast cancer in rats when using TENS, IFC or PBMT. Method: An experimental, randomized, controlled and cross-sectional study. With 90 days of age, 7,12-dimetylbenz(a)anthracene (7,12-DMBA) was administered to rats by gastric gavage to induce mammary cancer. After 120 days the mammary glands of the rats belonging to the group with mammary cancer were removed. Results: 39 female Sprague-Dawley rats were studied: 9 rats without induction of mammary carcinoma; 9 rats with induction of mammary carcinoma and without surgery; 9 rats with induction of mammary carcinoma with surgery and placebo application of TENS, IFC, PBMT; 9 rats with induction of mammary carcinoma, surgery and the application of TENS, IFC and PBMT. Conclusion: This study demonstrated that there was local recurrence of tumors in rats that were stimulated with TENS or IFC, however no evidence of local recurrence with PBMT.

Rasam (South Indian Spice Soup) - Attenuates the Mammary Tumor Induction Magnitude of 7,12-Dimethylbenz[a] anthracene in Sprague–Dawley Rats

Background: Recently, we have reported rasam (South Indian spice soup) for antiproliferative activity against Michigan Cancer Foundation-7 cell lines. Objectives: Breast cancer seems to be more common in the younger age group. Considering the deviation of the younger group from the traditional food habits as one of the many reasons of breast cancer incidence, rasam was investigated for its chemopreventive effect on mammary carcinoma. Materials and Methods: Rasam at 3 and 4 mL/kg dose was administered to female Spraque–Dawley rats for 30 days before 7,12-dimethylbenz[a] anthracene (DMBA) induction of mammary carcinoma. Tamoxifen was used as the standard drug. Body weight, thiobarbituric acid reactive substances (TBARSs), phase I enzymes, hexokinase (HK), aldolase (AD), glucose 6-phosphatase (G6P), fructose 1,6-bisphosphatase (F16P), citric acid cycle (CAC) enzymes, histopathology, tumor weight, tumor latency, and tumor incidence were studied. Results: In all the studied parameters such as body weight, TBARS, phase I enzymes, HK, AD, G6P, F16P, and CAC enzymes, rasam-pretreated groups showed better prevention than tamoxifen-treated groups. Histochemical findings also clearly confirm the chemopreventive effect of rasam. Particularly at the dose of 4 mL/kg, rasam was efficient in reducing the percentage of incidence of tumor, number of tumor, and tumor weight. Conclusion: The present study reveals that rasam attenuates the mammary tumor induction magnitude of DMBA in female rats.

Abstract 668: Induction of mammary carcinoma in tetracycline-inducible cMET(T1010I) transgenic mice

Abstract Gene amplification and mutations of cMET have been reported in a wide variety of tumors, including colorectal, lung, renal, liver, thyroid, and breast cancer. cMET(T1010I) mutation occurred in 5.2% out of 148 sibling pairs diagnosed with colorectal cancer in one study. This germline mutation occurs in about 1% of breast cancer patients, but its frequency increases to 2% in metastatic breast cancer. Furthermore, 16% of breast cancer cases with PI3KCA mutations have co-mutations of the cMET oncogene. To determine the functional consequences of this germline mutation and elucidate the molecular mechanisms of tumorigenesis induced by its oncogenic mutant protein, we developed a transgenic mouse model expressing human cMET(T1010I) under the control of a Tet-responsive promoter. MMTV promoter - directed expression of reverse tetracycline-controlled transactivator (rtTA) turns on the expression of the cMET(T1010I) transgene in murine mammary glands upon tetracycline administration. Thirty percent of these mice developed early onset mammary carcinoma within 5 months of transgene induction. This contrasts with previous reports of mammary tumor development in MMTV-cMET transgenic mice after more than a year. This strong phenotype is not the result of a random insertional effect of the transgene as no mammary tumors developed in the 29 transgene positive mice without mammary-specific expression of rtTA over a year in our study. Molecular characterization of these tumors is currently underway and the results may reveal mechanisms of tumorigenesis and novel therapeutic targets for patients harboring this mutation. In conclusion, we showed for the first time that the cMET(T1010I) mutation can trigger rapid breast tumorigenicity. By using organ-specific expression of rtTA to direct the expression of cMET(T1010I) in the organ of interest, our transgenic model may be used to understand the impact of cMET(T1010I) on many other cancer types such as colorectal, lung, renal, thyroid, and liver cancer. Citation Format: Chuanwei Yang, Ana M. Gonzalez, Naoto T. Ueno, Shuying Liu, Jinsong Zhang, Gordon B. Mills, John Mendelsohn, Prahlad Ram. Induction of mammary carcinoma in tetracycline-inducible cMET(T1010I) transgenic mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 668.

Effects of 4-n-Octylphenol on the Induction of Mammary Tumors Induced by 7,12-Dimethylbenz[a]anthracene in Rats

We previously reported that a neonatal administration of diethylstilbestrol or 17beta-estradiol affected the mammary carcinogenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) in rats. The aim of this present study was to investigate the effects of 4-n-octylphenol (OP), a weak estrogenic disruptor, on the induction of mammary carcinomas (MC) and benign proliferative lesions (PL) induced by DMBA in rats. All female rats were administered at 0, 0.1, 10, 100, and 1,000 microg OP once at birth, given 10 mg DMBA at 50 days after birth, and thereafter underwent necropsy at 351 days after birth. All male rats were given 10 mg DMBA at 28, 42, and 56 days after birth, and 0, 10, 100, and 1,000 ppm OP fed from day 70-153; they underwent necropsy at 153 days after birth. Neonatal single administration of OP in female rats showed no effects such as persistent estrus, anovulatory ovaries, or PL. A slight increase in numbers of rats with MC occurred at the highest dosage. Feeding a large dose of OP for a long period in male rats induced atrophy of testes and slightly increased numbers of affected MC but not increased numbers of males while it showed no effects on PL. These results suggested that administration of a large dose of OP for a long period may have had a minimal effect on mammary carcinogenesis in male rats.

Effects of Neonatally Administered High-dose Diethylstilbestrol on the Induction of Mammary Tumors Induced by 7,12-Dimethylbenz[a]anthracene in Female Rats

The aim of this study was to investigate the effects of neonatal administration of a relatively high dose of diethylstilbestrol (DES) on the induction of mammary carcinomas (MCs) and benign proliferative lesions (PLs) induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female rats. Three different terms of daily administration of DES (10 microg) were used: 0-14, 0-5, and 6-14 days after birth. Control animals were administered solvent (oil) alone once daily from 0 to 14 days after birth. Rats were given DMBA (10 mg) at 50 days after birth. All rats administered DES showed persistent estrus and anovulatory ovaries. In rats administered DES from 0 to 14 and 0 to 5 days after birth there was protection from development of MCs and PLs, and serum levels of both estrogen and progesterone were significantly lower than in the control animals at 100 days after birth. In rats administered DES from 6 to 14 days after birth, the incidence of MCs was equal to that of the control animals (100%), and the number of PLs was significantly higher than in the control animals. The critical period for exposure to endocrine disruptors, such as DES, affecting the induction of MCs and PLs may be from 0 to 5 days after birth.

Effects of Fetal Exposure to Diethylstilbestrol on Mammary Tumorigenesis in Rats

The aim of this study was to investigate the effect of fetal exposure to diethylstilbestrol (DES) on the induction of mammary tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female rats. Pregnant rats were fed only normal diet, diet mixed with 0.1 ppm DES throughout pregnancy period or diet mixed with 0.1, 1 or 10 ppm DES from day 13 of pregnancy till the end of pregnancy. Delivered pups were given 10 mg DMBA by gastric intubation at 50 days after birth and observed till 336 days after birth. Some rats exposed to DES throughout pregnancy and those from day 13 till the end of pregnancy showed endocrine disrupting effects such as absence of CL and active lactation in mammary glands at necropsy, while no abnormal estrus cycle such as persistent estrus was seen during the observation period until 88 days after birth. Fetal exposure to 0.1 ppm DES throughout pregnancy period, 0.1 and 1 ppm DES from day 13 of pregnancy increased the incidence and number of mammary carcinomas (MCs) at the earlier period while exposure to 0.1 ppm DES throughout pregnancy period enhanced the incidence and number of benign proliferative lesions (PLs) at the later period. MCs appeared earlier than benign PLs. These results suggest that exposure to DES throughout pregnancy and from day 13 of pregnancy could induce endocrine disrupting conditions and enhance the induction of MCs and that exposure to DES throughout pregnancy enhance PLs.

The Effects of Repeated Administration of 7,12-Dimethylbenz[a]anthracene on the Induction of Mammary Carcinomas and Dysplasias in Rats

The aim of this study was to investigate the effects of repeated administrations of relatively low doses of 7,12-dimethylbenz[a]anthracene (DMBA) on the induction of mammary carcinomas (MCs) and dysplasias (MDs) in rats. DMBA at 0, 0.1, 0.2, 0.5 and 1 mg for female rats, and at 0, 0.5, 1 and 2 mg for male rats was administered twice weekly after weaning. In female rats, repeated administration of 1 mg DMBA induced MCs while 0.1 mg DMBA induced MDs in all animals. The incidence of MCs increased and the latent period shortened while the incidence of MDs decreased in a dose-dependent manner. In male rats, repeated administration of 2 mg DMBA induced MCs in all animals. The incidence of MCs increased and the latent period shortened in a dose-dependent manner while the incidence of MDs increased by repeated administration of 1 mg DMBA. These results suggest that the total exposure of chemical carcinogens may be responsible for the induction of MCs or MDs, and that MDs may be more dependent on female sex hormones than MCs.

Effects of Neonatally Administered Diethylstilbestrol on Induction of Mammary Carcinomas Induced by 7, 12-Dimethylbenz[A]Anthracene in Female Rats

Various doses of diethylstilbestrol (DES) were administered to rats once at birth. Thereafter, at 50 days after birth, the rats in all groups were given 10 mg 7, 12-dimethylbenz[a]anthracene (DMBA) and undergone necropsy at 300 days after birth. The incidence of mammary carcinomas (MCs) were 50, 54, 91, 39, 19% at 175 days after birth, and 77, 87, 100, 85, 75% at necropsy in the 0, 0.1, 1, 10, 100 microg groups, respectively. The incidence of rats without corpus luteum were 0, 0, 0, 30, 100% at 50 days after birth, and 0, 40, 53, 93, 100% at necropsy in the 0, 0.1, 1, 10, 100 microg groups, respectively. Observation of the whole mount specimens showed a higher number of terminal end buds (TEBs) in the 1 microg group and a lower number in the 100 microg group compared with the control at 50 days after birth. It suggested that the administration of a relatively low dose (1 microg) of DES during neonatal period may increase TEBs, thus resulting in a stimulatory effect on the initiation of MCs.

Prophylactic effect of tamoxifen against induction of mammary carcinoma

Tamoxifen (TAM) is a potent anticancer agent known to interrupt the enhanced estrogen activity of malignant mammary gland cells, The mechanism of tamoxifen’s anti-tumor activity is primarily due to its anti estrogen action. Female Swiss albino mice were used in the present study and divided into:- normal control group, two Ehrlich ascites carcinoma (EAC) control groups [treated interaperitonealy(IP) and subcutaneously (Sc)], tamoxifen treated only group, tamoxifen pre treated then EAC (S.C) injected group and tamoxifen pre treated then EAC (I.P) injected group. The present results showed a significant decrease in tumor volume and a significant increase in the survival time in the pre-treated group compared to untreated group. There was a pathological change in the uterine tissues of the tamoxifen treated mice in the form of squamous metaplasia and dysplasia of glandular epithelial . The kidney tissues showed a minimal pathological change in the form of a focal renal lesion in the renal tubular epithelium. in conclusion the present study showed that tamoxifen has a prophylactic effect against experimental mammary carcinoma. And exerts some side effects on the histopathological structure of the uterine and kidney tissues. Key words: Tamoxifen, Mammary carcinoma, experimental, prophylactic, side effect.

Prophylactic effect of tamoxifen against induction of mammary carcinoma

Prophylactic effect of tamoxifen against induction of mammary carcinoma

Ductal growth is impeded in mammary glands of C-neu transgenic mice

The steroid hormone, estradiol, is essential for both the growth of normal breast and induction of mammary carcinomas. The growth promoting effects of estrogen are presumed to be mediated by growth factors, in particular, epidermal growth factor, which mediates its effects through erbB receptors, erbB1 and erbB2/C-neu. C-neu is amplified and over-expressed in a large number of human cancers and transgenic mice over-expressing C-neu also develop mammary tumors. However, as yet, the impact of C-neu over-expression on estrogen action during normal mammary development and hence, its precise role in carcinogenesis, remains unclear. In the present studies, we demonstrate that estradiol-dependent mammary ductal growth accompanying puberty is impaired in transgenic mice expressing wild type Cneu, and is intrinsic to the tissue. The impairment is not due to an overall impairment in estrogen action, since progesterone receptor expression is unaffected in C-neu mice. It is also not due to an intrinsic inability of the epithelial cells to proliferate, since impeded ductal growth co-exists with alveolar growth during pregnancy. Therefore, we propose that, depending on the physiological state, C-neu may either promote or inhibit the growth of mammary epithelial cells, and discuss its potential significance to carcinogenesis.

Effects of High Doses of 17.BETA.-estradiol and Ovariectomy on 7,12-Dimethylbenz[a]anthracene-Induced Mammary Carcinomas and Dysplasias in Neonatally Androgenized Female Sprague-Dawley Rats.

Inbred, female Sprague-Dawley rats were neonatally androgenized at the age of 2 days by subcutaneous injections of 1.25 mg testosterone propionate and divided into 4 groups. At the age of 50 days, rats of all groups were given 20 mg 7, 12-dimethylbenz[a]anthracene (DMBA). Four weeks after the administration of DMBA, the rats in Group I remained intact, those in Group II were subjected to ovariectomy, while the animals in Groups III and IV were given 1 mg 17β-estradiol (E2) at 2-day intervals for 3 weeks. Additionally, the rats in Group IV were given 1 mg E2 at 2-day intervals for 3 weeks by intramuscular injection, starting from the 105th day after the administration of DMBA.The ovaries of the neonatally androgenized rats contained numerous large vesicular follicles and no corpora lutea, and the mammary glands of the animals in Groups I, III and IV consisted mainly of dilated acini containing milky secretions. In rats in Group I, mammary carcinomas and mammary dysplasias were induced. Rat mammary dysplasias were grossly characterized by gross cysts and solid masses. Solid masses were heteromorphic lesions and commonly consisted of several nodules with various microscopic features. These masses were subclassified into the 2 types of histological features that were predominant among the nodules: acinar adenosis and fibrotic adenosis. The induction of mammary carcinomas and mammary dysplasias was strongly suppressed by ovariectomy (Group II) as the development of mammary carcinomas and mammary dysplasias induced in neonatally androgenized rats are dependent on estrogens. The induction of mammary carcinomas was suppressed by injections of high doses of E2 for 21 days (Once in Group III and twice in Group IV). Conversely, the induction of mammary dysplasias was promoted by one time (Group III) but was suppressed by two times (Group IV) of E2. The results indicate that carcinoma cells and dysplasia cells induced by DMBA in neonatally androgenized rats differ in response to high doses of E2.

The Effects of Sex Hormones on the Induction of Mammary Carcinomas in Male Rats by Pulse Doses of 7,12-Dimethylbenz(a) anthracene.

Male Sprague-Dawley rats were orally dosed with 10 mg 7, 12-dimethylbenz(a)anthracene 3 or 5 times at 14-day intervals starting from 28 days of age. The male rats were treated with various hormonal treatments such as castration and/or injections (3 times/week) of various doses of 17β-estradiol or progesterone, 14 days after the last administration of 7, 12-dimethylbenz(a)anthracene. Extreme secretion in the wide lumina of the acini of the mammary glands was observed in rats given injections at high doses (0.1 mg and 1 mg) of 17β-estradiol. However, there was little lumina of acini without secretion in developed mammary glands in rats given injections of progesterone. This feature of the mammary glands suggests increased levels of progesterone and estrogens in rats given injections of progesterone because of the conversion of progesterone to estrogen. Number of rats with carcinoma and number of carcinoma per rat increased extremely and slightly in rats given injections of 0.01 mg 17β-estradiol or injections of 4 mg progesterone and in rats given injections of high doses (0.1 mg and 1 mg) of 17β-estradiol, respectively. These results indicate that suitable doses of estrogen, particularly 0.01 mg 17β-estradiol promote the progression of male mammary carcinogenesis. In rats given injections of high doses (0.1 mg and 1 mg) of 17β-estradiol, the number of carcinomas with squamous metaplasia increased significantly, and the number of estrogen receptor-positive carcinomas decreased extremely when cells with nuclei stained by immunohistochemical methods were interpreted as positive cells, and a tumor with 20% of positive cells was considered estrogen receptor-positive.

The Influence of Estrogen Treatment on Induction of Mammary Carcinoma in Rats by Single-Dose Gamma Irradiation at Different Ages

The effect of age at exposure on induction of mammary carcinoma was studied in female rats of the inbred WAG/Rij strain that were treated with estrogen. Groups of 40 animals were exposed to a single total-body dose of 1 or 2 Gy of 137Cs gamma radiation at age 8, 10, 12, 15, 22, 36 or 64 weeks. Hormone levels in the animals were increased by implantation of a pellet containing Estradiol-17beta 2 weeks prior to irradiation. Animals were killed when moribund. All mammary tumors were resected and classified histologically as carcinoma or fibroadenoma. The age-specific incidence of mammary carcinoma was compared with that in control groups of unirradiated estrogen-treated rats using lifetime statistical analysis with both parametric and nonparametric methods. The excess normalized risk of carcinoma was 7.7 for both 1 and 2 Gy in the age groups 8-15 weeks, with no significant differences between the age groups. However, in the age groups 22-64 weeks, the excess normalized risk decreased with increasing age at exposure. Irradiation at 64 weeks yielded fewer carcinomas than in the controls, with an excess normalized risk of -0.6 for both 1 and 2 Gy. The excess normalized risk was 10-80 in estrogen-treated controls compared to untreated rats. The present data agree with the results reported previously for estrogen-treated rats irradiated at ages 8 or 17 weeks with doses of 0.3 or 1.2 Gy. The reduced risk of radiation exposure at midlife observed in this study in hormone-treated rats has also been reported for animals not treated with estrogens. The present findings support the earlier conclusion that radiological screening for mammary cancer after the age of menopause will not increase the normal incidence of breast cancer. Estrogen treatment at midlife may increase the risk of breast cancer in women using replacement estrogens during and after menopause.

Dose-dependent induction of mammary carcinomas in female Sprague-Dawley rats with 2-amino-1-methyl-6-phenylimidazol[4,5-b]pyridine.

The dose‐dependence of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) induction of mammary carcinomas was investigated in female Sprague‐Dawley (SD) rats given PhIP in the diet for 48 weeks at concentrations of 0, 25, 100 and 200 ppm in experiment 1, and 0, 12.5, 50 in experiment 2. Yields of ductular lesions, including intraductal papillomas and carcinomas, as well as papillo‐tubular and solid‐tubular carcinomas, showed dependence on the dose, with the respective total incidences being 0, 4.8, 25, 72.2 and 0, 10 and 35%. There was thus no apparent carcinogen exposure threshold. The present results confirmed the carcinogenicity demonstrated in a previous study using F344 rats and revealed the SD rat strain to be more susceptible.

Serum cross-reactive thymosin a1 levels in rats during induction of mammary carcinoma with 7,12-dimethylbenz[ a]anthracene: short- and long-term effects

The levels of serum cross-reactive thymosin a 1 (CRT a 1) were measured at various time intervals during the course of development of mammary tumors in female Sprague-Dawley rats intubated with 7,12-dimethylbenz[ a]-anthracene (DMBA; 10 mg/rat). Matched control rats were also tested simultaneously. An increase in CRT a 1 in DMBA-treated animals was observed within 2 h of DMBA treatment. Thereafter the levels of CRT a 1 in the serum of the DMBA-treated rats remained elevated for another 3 weeks prior to declining to control levels. Levels remained stationary until an increase in serum CRT a 1 was observed at 9–11 weeks post-DMBA treatment. This correlated with the time when mammary tumors were either palpable or observed. Levels of CRT a 1 fell at 13 weeks but remained slightly elevated until sacrifice due to tumor burden at 18 weeks.

Influence of estrogen and progesterone on the induction of mammary carcinomas by 7,12-dimethylbenz(a)anthracene in ovariectomized rats.

The influence of estrogen on mammary carcinogenesis was studied in female Sprague-Dawley rats ovariectomized at the age of 36 days and given injections of 17 beta-estradiol (group I:0, II:1, III:10, IV:100, V:1000 micrograms/2 days) between the ages of 36 and 250 days and a single oral dose of 20 mg of 7,12-dimethylbenz(a)anthracene (DMBA) at the age of 50 days. No palpable mammary carcinomas were detected up to the age of 135 days. At the age of 135 days, each group was divided into two subgroups (a and b). Rats of the second subgroup (Ib, IIb, IIIb, IVb and Vb) were given additional injections of progesterone (P; 4 mg/2 days) between the ages of 135 and 250 days. At the age of 250 days, the incidence of mammary carcinoma was significantly higher in rats from group IIIb than in groups Ib and IIIa, and that in group IVa was also higher than in group Ia. The incidence in group IVb was significantly lower than in group IVa. The carcinomas in group IIIb were palpable papillo-tubular adenocarcinomas and those in group IVa were secretory micro-adenocarcinomas. These results indicate that the induction of mammary carcinomas by DMBA is totally inhibited by ovariectomy and/or high doses of estrogen, but that mammary carcinomas are initiated by DMBA under hormonal conditions in which suitable levels of estrogen are present. They also suggest that the growth of DMBA-induced mammary carcinomas in the rats from group III were accelerated by additional injections of P and that those in rats from group IV were inhibited by additional P.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum poly(A)polymerase levels in rats during induction of mammary carcinoma with 7,12-dimethylbenz[ a]anthracene

Levels of activity of poly(A)polymerase (polynucleotide adenylyl transferase), the enzyme responsible for the addition of poly(A) tracts to the 3′-termini of eukaryotic mRNAs were assayed in the serum of rats during induction of mammary carcinoma by intragastric administration of 7,12-dimethylbenz[ a]anthracene (DMBA, 10 mg/rat). An appreciable rise in the levels of poly(A)polymerase coincided with the growth of palpable DMBA-induced mammary carcinoma, which then dropped sharply 2 weeks later when the tumor incidence reached its peak of 65%.

Oncogenes, cancer and analytical cytology.

Oncogenes, cancer and analytical cytology.

Direct mutagenesis of Ha-ras-1 oncogenes by N-nitroso-N-methylurea during initiation of mammary carcinogenesis in rats.

Induction of mammary carcinomas in rats by a single exposure to a carcinogen during sexual development often involves malignant activation of the Ha-ras-1 locus. Each of the Ha-ras-1 oncogenes present in tumours induced by N-nitroso-N-methylurea, but not in those induced by 7,12-dimethylbenz(a)anthracene, became activated by the same G----A transition, the type of mutation induced by N-nitroso-N-methylurea. These results are consistent with the notion that Ha-ras-1 oncogenes are directly activated by the carcinogen during initiation of neoplasia.