Development Of Mammary Carcinoma Research Articles

Cis-9, trans-11 CLA Derived Endogenously from trans-11 18:1 Reduces Cancer Risk in Rats

The present study was designed to examine the effects of increasing dietary levels of vaccenic acid (VA) and cis-9, trans-11 conjugated linoleic acid (CLA) on chemically induced mammary carcinogenesis in rats. Both fatty acids were provided as a natural component in butter fat. The conversion of VA to CLA by delta9-desaturase was documented previously in several species, including rats and humans. Specifically, our objective was to determine the relative contribution of dietary VA and CLA to the tissue concentration of CLA and its ability to inhibit the development of mammary carcinomas. A total of 7 diets were formulated with varying levels of CLA and VA. The overall dietary treatment scheme was designed to evaluate the modulation of mammary cancer risk by 1). small increases of CLA in the presence of a low level of VA and 2). more substantial increases of VA against a background of low levels of CLA. As expected, small increases in dietary CLA at the low end of the CLA dose-response range did not reduce tumorigenesis. In contrast, there was a distinct and marked inhibitory response to VA that was dose dependent. The effect of VA was magnified in this experiment because the dose range of VA tested was much broader than that of CLA. Fatty acid analysis showed that the conversion of dietary VA to CLA resulted in a dose-dependent increase in the accumulation of CLA in the mammary fat pad, which was accompanied by a parallel decrease in tumor formation in the mammary gland. The finding confirms that the conversion of VA to CLA is as important for cancer prevention as the dietary supply of CLA. Thus, VA is also anticarcinogenic, and VA and CLA represent functional food components that are present in ruminant fat.

PRb2/p130-E2F4/5-HDAC1-SUV39H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1 multimolecular complexes mediate the transcription of estrogen receptor-alpha in breast cancer.

The estrogen receptor-alpha (ER) plays a crucial role in normal breast development and is also linked to development and progression of mammary carcinoma. The transcriptional repression of ER-alpha gene in breast cancer is an area of active investigation with potential clinical significance. However, the molecular mechanisms that regulate the ER-alpha gene expression are not fully understood. Here we show a new molecular mechanism of ER-alpha gene inactivation mediated by pRb2/p130 in ER-negative breast cancer cells. We investigated in vivo occupancy of ER-alpha promoter by pRb2/p130-E2F4/5-HDAC1-SUV39 H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1 complexes, and provided a link between pRb2/p130 and chromatin-modifying enzymes in the regulation of ER-alpha transcription in a physiological setting. These findings suggest that pRb2/p130-multimolecular complexes can be key elements in the regulation of ER-alpha gene expression and may be viewed as promising targets for the development of novel therapeutic strategies in the treatment of breast cancer, especially for those tumors that are ER negative.

Immunotherapy of spontaneous mammary carcinoma with fusions of dendritic cells and mucin 1-positive carcinoma cells.

The tumour-associated antigen mucin 1 (MUC1) is a multifunctional protein involved in protection of mucous membranes, signal transduction, and modulation of the immune system. More than 70% of cancers overexpress MUC1, making MUC1 a potential target for immunotherapy. In the present study, MUC1 transgenic mice were crossed with syngeneic strains that express the polyomavirus middle-T oncogene (PyMT) driven by the mouse mammary tumour virus promoter long-terminal repeat (MMTV-LTR). The resultant breed (MMT mice) developed spontaneous MUC1-expressing mammary carcinomas with 100% penetrance at 8-15 weeks of age. As found in human breast cancer, the mammary carcinoma in MMT mice arose in multiple stages. Immunization with fusions of dendritic cells and MUC1-positive tumour cells (FC/MUC1) induced MUC1-specific immune responses that blocked or delayed the development of spontaneous breast carcinomas. In contrast, there was no delay of tumour development in MMT mice immunized with irradiated MC38/MUC1 tumour cells. The efficacy of fusion cells was closely correlated with the timing of initial immunization. Immunization with FC/MUC1 initiated in MMT mice at < 1, 1-2 and 2-3 months of age rendered 33, 5 and 0% of mice free of tumour, respectively, up to 6 months. Whereas mice immunized in the later stage of tumour development succumbed to their disease, immunization resulted in control of tumour progression and prolongation of life. These results indicate that immunization with FC/MUC1 can generate an anti-MUC1 response that is sufficient to delay the development of spontaneous mammary carcinomas and control tumour progression in MMT mice.

Number of pregnancies and ovariectomy modify mammary carcinoma development in transgenic HER-2/neu female mice

We studied effect of pregnancy and ovariectomy on the development of mammary tumors in homozygous female HER-2/neutransgenic mice. The mean life span of uniparous mice was decreased by 16% in comparison to the control ( P<0.05) and of mice which have two pregnancies decreased by 11% ( P<0.05). Ovariectomy at the age of 2 months was followed by 32.7% increase in mean life span of mice. The incidence or multiplicity of mammary adenocarcinomas did not change in uniparous mice, whereas the size of the tumors and metastatic potential were decreased as compared to the virgins. When mice have two full-time pregnancies, there was an increase in multiplicity of mammary carcinomas and significant (2.1-fold) decrease in the survival time of tumor-bearing mice. Ovariectomy significantly decreased the total incidence of mammary carcinomas, the number of tumors per tumor-bearing animal, and inhibited metastasizing into lungs. Our results indicate that pregnancy accelerated the development of mammary adenocarcinomas in transgenic HER-2/neu mice whereas ovariectomy inhibits their development.

Prevention of spontaneous breast carcinoma by prophylactic vaccination with dendritic/tumor fusion cells.

Genetically modified mice with spontaneous development of mammary carcinoma provide a powerful tool to study the efficacy of tumor vaccines, since they mimic breast cancer development in humans. We used a transgenic murine model expressing polyomavirus middle T oncogene and mucin 1 tumor-associated Ag to determine the preventive effect of a dendritic/tumor fusion cell vaccine. The MMT (a transgenic murine model) mice developed mammary carcinoma between the ages of 65-108 days with 100% penetrance. No spontaneous CTL were detected. However, prophylactic vaccination of MMT mice with dendritic/tumor fusion cells induced polyclonal CTL activity against spontaneous mammary carcinoma cells and rendered 57-61% of the mice free of the disease at the end of experiment (180 days). Furthermore, the level of CTL activity was maintained with multiple vaccinations. The antitumor immunity induced by vaccination with dendritic/tumor fusion cells reacted differently to injected tumor cells and autochthonous tumor. Whereas the injected tumor cells were rejected, the autochthonous tumor evaded the attack and was allowed to grow. Collectively these results indicate that prophylactic vaccination with dendritic/tumor fusion cells confers sufficient antitumor immunity to counter the tumorigenesis of potent oncogenic products. The findings in the present study are highly relevant to cancers in humans.

Constitutive telomerase expression promotes mammary carcinomas in aging mice.

Telomerase is up-regulated in the vast majority of human cancers and serves to halt the progressive telomere shortening that ultimately blocks would-be cancer cells from achieving a full malignant phenotype. In contrast to humans, the laboratory mouse possesses long telomeres and, even in early generation telomerase-deficient mice, the level of telomere reserve is sufficient to avert telomere-based checkpoint responses and to permit full malignant progression. These features in the mouse provide an opportunity to determine whether enforced high-level telomerase activity can serve functions that extend beyond its ability to sustain telomere length and function. Here, we report the generation and characterization of transgenic mice that express the catalytic subunit of telomerase (mTERT) at high levels in a broad variety of tissues. Expression of mTERT conferred increased telomerase enzymatic activity in several tissues, including mammary gland, splenocytes, and cultured mouse embryonic fibroblasts. In mouse embryonic fibroblasts, mTERT overexpression extended telomere lengths but did not prevent culture-induced replicative arrest, thus reinforcing the view that this phenomenon is not related to occult telomere shortening. Robust telomerase activity, however, was associated with the spontaneous development of mammary intraepithelial neoplasia and invasive mammary carcinomas in a significant proportion of aged females. These data indicate that enforced mTERT expression can promote the development of spontaneous cancers even in the setting of ample telomere reserve.

Mammary Carcinomas Induced in Human c‐Ha‐ras Proto‐oncogene Transgenic Rats Are Estrogen‐independent, but Responsive to d‐Limonene Treatment

We have previously shown that transgenic rats carrying three copies of the human c‐Ha‐ras proto‐ oncogene (Hras128) are highly susceptible to N‐methyl‐N‐nitrosourea (MNU) mammary carcino‐ genesis. All transgenic rats treated with 50 mg/kgMNU, i.v. at 50 days of age, were found to rapidly develop multiple, large mammary carcinomas within as short a period as 8 weeks. In the present study, the effects of ovariectomy and treatment with d‐limonene, known to inhibit mammary carcinogenesis in non‐transgenic female rats, were investigated in Hras128 animals treated withMNU to clarify the role of the human c‐Ha‐ras proto‐oncogene and to characterize the induced mammary carcinomas. Although ovariectomy completely inhibited development of mammary carcinomas in their wild‐type counterparts, it did not affect either the incidence or the multiplicity of the mammary carcinomas in the Hras128 rats. On the other hand, treatment with d‐limonene, an inhibitor of ras protein isoprenylation, inhibited the breast tumor development. These results indicate that aberrant c‐Ha‐ras gene expression is involved in ovarian hormone‐independent growth and c‐Ha‐ras protein isoprenylation plays an important role in mammary carcinogenesis

Expression of the adhesion molecule CEACAM1 (CD66a, BGP, C-CAM) in breast cancer is associated with the expression of the tumor-suppressor genes Rb, Rb2, and p27.

The adhesion molecule CEACAM1 (CD66a, BGP, C-CAM) is not only involved in maintaining normal tissue architecture, but also acts as a tumor suppressor in several experimental systems where loss of CEACAM1 expression results in enhanced tumor-cell growth and tumorigenicity. In order to further analyze the role of CEACAM1 in the development of breast cancer, we performed Western-blot analysis and immunohistochemistry with highly specific monoclonal antibodies in a cohort of 68 mammary carcinomas which had also been analyzed for expression of cell-cycle regulatory proteins cyclin D1, cyclin E, p16, p21, p27, Rb, and Rb2, as well as for steroid hormone receptor status, Ki67, and HER2/neu immunoreactivity. High CEACAM1 protein expression as found using both methods correlated significantly with expression of the retinoblastoma proteins Rb (P=0.004 and 0.013) and Rb2/p130 (P=0.003 and 0.007). In addition, we found a weak association of CEACAM1 expression with p27 protein levels (P=0.087 and 0.039), but with none of the other analyzed parameters. These results indicate the possibility of a functional link between cell-adhesion molecules and cell-cycle regulation that might play an important role in the development of mammary carcinomas.

Tibolone: a compound with tissue specific inhibitory effects on sulfatase

The aim was to test whether sulfatase activity is differently regulated by tibolone in human bone, endometrium and breast cells since selective inhibition of sulfatases in various tissues may contribute to the tissue-specificity of tibolone. Tibolone, its 3α- and 3β-hydroxy metabolites and their 3-sulfated forms, and its Δ 4-isomer strongly (70–90%) inhibited the sulfatase activity in human breast cell lines (two T-47D clones) and intermediately (8–43%) in human endometrial cells (HEC-1A). In contrast, they did not inhibit sulfatase in two human osteoblast-like cell lines (MG 63, HOS TE-85). The specific sulfatase inhibitor, EMATE, showed inhibition in all cell lines. Just as estrone sulfate, 3α-sulfated tibolone was also converted by sulfatase to the unconjugated 3α-hydroxy-tibolone intracellularly in all cell lines. The tissue specific inhibition pattern of sulfatase activity by tibolone and its metabolites suggest that tibolone could be protective against development of mammary carcinomas, whereas it retains favorable estrogenic effects on bone.

Uptake and Metabolism of Hydroxymatairesinol in Relation to Its Anticarcinogenicity in DMBA-Induced Rat Mammary Carcinoma Model

The chemopreventive effects of hydroxymatairesinol (HMR), a lignan extracted from Norway spruce (Picea abies), on the development of mammary carcinoma induced by 7,12-dimethylbenz[a]anthracene (DMBA) was studied in rats. HMR administered via diet in an average daily dose of 4.7 mg/kg body wt starting before DMBA induction reduced tumor volume and tumor growth, but no significant reduction in tumor multiplicity (number of tumors/rat) was observed. The predominant histological type in the control group was type B (well-differentiated adenocarcinoma, 78%). The proportion of type B tumors decreased to 35% in the HMR group, while the type A (poorly differentiated) and type C (atrophic) tumor proportions increased. Anticarcinogenic effects of dietary HMR (4.7 mg/kg) were also evident when the administration started after DMBA induction and was seen as growth inhibition of established tumors. Dietary HMR supplementation significantly increased serum and urinary enterolactone and HMR concentrations but had no significant effect on the uterine weight, suggesting that HMR or its major metabolite enterolactone did not have an antiestrogenic effect. Further studies are warranted to further clarify and verify HMR action and the associated mechanisms in mammary tumorigenesis.

Chemoprevention by nimesulide, a selective cyclooxygenase-2 inhibitor, of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary gland carcinogenesis in rats.

Breast cancer is common in women all over the world, and exploration of chemopreventive approaches to this cancer is very important. Nimesulide, a selective inhibitor of cyclooxygenase‐2 (COX‐2), is a good candidate as a chemopreventive agent with low toxicity. We examined its effects on mammary tumor development in female Sprague‐Dawley rats induced with the environmental carcinogen 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP). Rats at 7 weeks of age received intragastric intubations of PhIP (85 mg/kg body weight) 4 times weekly for 2 weeks and were maintained on control diet (high fat diet) or experimental diet (high fat diet supplemented with 400 ppm nimesulide) throughout the experiment. COX‐2 protein was over‐expressed in epithelial cancer cells and stromal cells of the PhIP‐induced mammary carcinomas, but was weak or not apparent in normal mammary gland cells. The development of mammary carcinomas was clearly suppressed by administration of nimesulide. The carcinoma incidence was 51% as compared to 71% for the control diet group. The average multiplicity of carcinomas in the experimental diet group was 1.2±0.2 (P < 0.05), significantly smaller than the control diet group value (2.6±0.5). The size of carcinomas was also clearly decreased; 1.1±0.4 cm3/rat in experimental diet group (P < 0.05), 4.1±1.3 cm3/rat in the control diet group. The results therefore provide evidence that the selective COX‐2 inhibitor, nimesulide, possesses chemopreventive activity against PhIP‐induced mammary carcinogenesis in rats.

Transforming growth factor alpha- and c-myc-induced mammary carcinogenesis in transgenic mice.

The growth factor transforming growth factor alpha (TGFalpha) and the nuclear transcription factor c-myc often are overexpressed by human breast cancer cells. To produce models of breast disease with these etiologies, mice were generated that carried TGF-alpha- or c-myc-encoding transgenes. Transgene targeting employed the whey acidic protein (WAP) gene promoter, which is expressed in pregnant and lactating mammary epithelial cells. Non-virgin WAP-TGFalpha transgenic mice displayed accelerated mammary development during pregnancy, delayed post-parturient mammary involution, a progressive increase in the number of hyperplastic alveolar nodules (HANs), and development of mammary carcinoma with a mean latency of 9 months. Non-virgin WAP-c-myc transgenic mice displayed accelerated mammary gland development during pregnancy and development of mammary carcinomas with a latency of 8 months. Bitransgenic mice carrying both WAP-TGFalpha and WAP-c-myc displayed a dramatic acceleration of tumor development. These models identify the overexpression of TGFalpha or c-myc as etiological factors in the development of mammary neoplasia and demonstrate the increased severity of disease when both molecular alterations are present in the same cell.

Influence of perinatal genistein exposure on the development of MNU-induced mammary carcinoma in female Sprague–Dawley rats

Genistein, a phytoestrogen, was subcutaneously (s.c.) injected to pregnant Sprague–Dawley CD rats on gestational days 16–20 at either 25 mg (Group 1) or 5 mg/day (Group 2). Female offspring of mothers not exposed to genistein during pregnancy received 12.5 mg genistein s.c. at neonatal days 15 and 18 (Group 3), or received vehicle only (Group 4). At 35 days of age, 4–9 female offspring from each group were autopsied to observe the influence of genistein, and remainder of female offspring received 50 mg/kg N-methyl- N-nitrosourea (MNU) intraperitoneally and were sacrificed when mammary tumors were larger than 1 cm in size or when they reached 35 weeks of age. Genistein treatment during the perinatal period resulted in lower body weight and lower relative uterine-ovarian weight at 35 days, and a prolonged estrus cycle with a long estrus phase at 12–16 weeks. However, at 35 days (time at MNU administration), mammary gland development, cell proliferation rate (PCNA labeling index), and the number of estrogen receptor (ER)- and progesterone receptor (PgR)-positive cells were similar between genistein-treated and untreated rats. Twenty-five or 5 mg genistein/day in utero (between days 16 and 20 of gestation) or 12.5 mg genistein/day on neonatal days 15 and 18 did not affect the incidence of mammary tumors >1 cm or the latency but did increase the number of mammary cancer lesions when MNU was administered at the time when the mammary gland growth in genistein-treated and untreated rats was similar. Thus, perinatal genistein is an endocrine disrupter and increases the multiplicity of MNU-induced mammary carcinoma in rats.

Rat models of premalignant breast disease.

While a number of agents have been shown to induce mammary carcinogenesis in the rat, premalignant stages of the disease have been best characterized in chemically-induced models, specifically those initiated by either 7,12 dimethylbenz[alpha]anthracene (DMBA) or 1-methyl-1-nitrosourea (MNU). In general, it appears that epithelial cells in mammary terminal end buds or terminal ductules are the targets of carcinogenic initiation, and that a series of morphologically identifiable steps are involved in the development of mammary carcinoma. The premalignant steps include ductal hyperplasia of the usual type and carcinoma in situ of the cribriform or comedo type; atypical ductal hyperplasia has not been reported. Thus the histogenesis of lesions occurring in chemically induced mammary carcinogenesis in the rat is similar to that observed in the human; although, the spectrum of lesions observed in the rat is limited. Opportunities to investigate the biological and molecular characteristics of premalignant breast disease in the rat are presented.

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.

Conjugated linoleic acid and other anticarcinogenic agents of bovine milk fat.

Prevention is an important strategy for conquering cancer. Milk fat contains a number of components, such as conjugated linoleic acid, sphingomyelin, butyric acid, ether lipids, beta-carotene, and vitamins A and D that have anticancer potential. Conjugated linoleic acid inhibits the growth of a number of human cancer cell lines and suppresses chemically-induced tumor development at a number of sites in animal models. As little as 0.1% of dietary conjugated linoleic acid inhibits the development of rat mammary tumors, independent of the amount and type of fat in the diet. Sphingomyelin, through its metabolites ceramide and sphingosine, participates in multiple antiproliferative pathways associated with suppression of carcinogenesis. Dietary sphingomyelin inhibits murine colon tumor development. Butyric acid, uniquely present in ruminant milk, is a potent antineoplastic agent and may ameliorate its potency through synergy with other milk fat components. Dietary butyric acid inhibits mammary carcinoma development in rats. In humans, ether lipids, beta-carotene, and vitamins A and D are associated with anticancer effects. Cows have the ability to extract anticarcinogenic components from pasture and feed and transfer them to milk. Use of genetic engineering and other techniques to increase the range and level of anticarcinogens in pasture and supplements may increase the anticancer potential of milk.

Genetic identification of multiple loci that control breast cancer susceptibility in the rat.

We have used a rat model of induced mammary carcinomas in an effort to identify breast cancer susceptibility genes. Using genetic crosses between the carcinoma-resistant Copenhagen (COP) and carcinoma-sensitive Wistar-Furth rats, we have confirmed the identification of the Mcs1 locus that modulates tumor number. We have now also identified two additional loci, Mcs2 and Mcs3. These three loci map to chromosomes 2, 7, and 1, respectively, and interact additively to suppress mammary carcinoma development in the COP strain. They are responsible for a major portion of the tumor-resistant phenotype of the COP rat. No loss of heterozygosity was observed surrounding the three loci. A fourth COP locus, Mcs4, has also been identified on chromosome 8 and acts in contrast to increase the number of carcinomas. These results show that mammary carcinoma susceptibility in the COP rat is a polygenic trait. Interestingly, a polymorphism in the human genomic region homologous to the rat Mcs4 region is associated with an increased breast cancer risk in African-American women. The isolation of the Mcs genes may help elucidate novel mechanisms of carcinogenesis, provide information important for human breast cancer risk estimation, and also provide unique drug discovery targets for breast cancer prevention.

Estrogen regulation of cell cycle progression in breast cancer cells

Estrogens are potent mitogens in a number of target tissues including the mammary gland where they play a pivotal role in the development and progression of mammary carcinoma. The demonstration that estrogen-induced mitogenesis is associated with the recruitment of non-cycling, G 0, cells into the cell cycle and an increased rate of progression through G 1 phase, has focused attention on the estrogenic regulation of molecules with a known role in the control of G 1–S phase progression. These experiments provide compelling evidence that estrogens regulate the expression and function of c-Myc and cyclin D1 and activate cyclin E-Cdk2 complexes, all of which are rate limiting for progression from G 1 to S phase. Furthermore, these studies reveal a novel mechanism of activation of cyclin E-Cdk2 complexes whereby estrogens promote the formation of high molecular weight complexes lacking the CDK inhibitor p21. Inducible expression of either c-Myc or cyclin D1 can mimic the effects of estrogen in activating the cyclin E-Cdk2 complexes and promoting S phase entry, providing evidence for distinct c-Myc and cyclin D1 pathways in estrogen-induced mitogenesis which converge on the activation of cyclin E-Cdk2. These data provide new mechanistic insights into the known mitogenic effects of estrogens and identify potential downstream targets that contribute to their role in oncogenesis.

Estrogen-induced tumorigenesis in the Copenhagen rat: disparate susceptibilities to development of prolactin-producing pituitary tumors and mammary carcinomas

The Copenhagen (COP) rat is unique among inbred rat strains in its high degree of resistance to spontaneously arising and induced mammary cancers. Hyperprolactinemia resulting from tumors of the anterior pituitary gland has been suggested to be the causative factor in the etiology of estrogen-induced mammary cancer in rats. Therefore, we have examined the ability of administered estrogens to induce development of PRL-producing pituitary tumors and mammary carcinomas in COP rats. Diethylstilbestrol (DES), administered to male COP rats for 12 weeks, beginning when the animals were 9 weeks of age, induced development of PRL-producing pituitary tumors, defined as grossly enlarged pituitary masses displaying lactotroph hyperplasia and associated hyperprolactinemia. When treated with 17 β-estradiol (E2), female COP rats developed pituitary tumors and hyperprolactinemia, but displayed a high degree of resistance to development of mammary carcinomas. These data indicate that E2-induced hyperprolactinemia is insufficient to induce development of mammary carcinomas in the female COP rat.

Effect of wheat bran fiber on the development of mammary tumors in female intact and ovariectomized rats treated with 7,12-dimethylbenz(a)anthracene and in mice with spontaneously developing mammary tumors.

We examined the effect of consumption of graded increases of dietary fiber (soft white wheat bran) on the development of mammary gland carcinomas in intact female Sprague-Dawley rats during the promotion stage of carcinogenesis, induced with 7,12-dimethylbenz(a)anthracene (DMBA). The percent of rats with mammary carcinomas, the total number of mammary carcinomas and the mean number of mammary carcinomas per rat were reduced significantly at all fiber levels examined compared to rats fed a control diet. Inclusion of 9.6% fiber in the diets of ovariectomized rats that had been treated with a single i.v. dose of 2.5 mg DMBA/100 g body weight 2 weeks prior to removal of the ovaries resulted in a significant decrease of carcinomatous and benign mammary tumors compared to ovariectomized rats fed a control diet. Development of spontaneous mammary carcinomas in virgin C3H/HeOuJ female mice and growth of a transplantable mammary gland tumor in such mice were reduced by inclusion of 9.6% fiber in the diet, a reduction that was significant or just barely missed significance, depending on the source of the fiber. Our observations provide evidence that inclusion of soft white wheat bran in the diet is effective in the suppression of mammary gland tumorigenesis in an array of experimental animal models.