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.

Growth requirements and neoplastic transformation of two types of normal human breast epithelial cells derived from reduction mammoplasty.

A chemically defined culture medium was developed to support the growth of two distinctly different types of normal human breast epithelial cells (HBEC) derived from reduction mammoplasty. Type I cells expressed luminal epithelial cell markers and were deficient in gap junctional intercellular communication (GJIC), whereas Type II cells expressed basal epithelial cell markers and were efficient in GJIC. In this study, we examined and compared the growth factor and hormone requirements of these two types of cells and a series of cell lines that were obtained by sequential transfection with SV40 DNA (extended lifespan, nontumorigenic), treatment with 5-bromodeoxyuridine (BrdU)/black light (immortal and weakly tumorigenic), and infection of a virus carrying the neu oncogene (highly tumorigenic). Growth of Type I cells was inhibited by withdrawing epidermal growth factor (EGF), hydrocortisone (HC), or insulin (INS) from the culture media, but was enhanced by fetal bovine serum (FBS) supplementation. Growth of Type II cells was inhibited by withdrawal of EGF, HC, or INS from the media, and was inhibited by FBS supplementation. Withdrawal of human transferrin (HT) or 17 beta-estradiol (E2) from the media did not alter the growth of Type I or Type II cells. SV40 transfected Type I cell lines still required EGF, HC, or INS for optimal growth. However, the highly tumorigenic cell line did not show a growth dependence on EGF, HC, or INS but did appear to require HT and 3,3',5-triiodo-D.L. thyronine (T3) for optimal growth. In addition, FBS stimulated the growth of these cell lines. Thus, this study shows that Type I HBEC are distinctly different from Type II HBEC in growth response to FBS and that neoplastically transformed Type I cells could become growth factor and hormone independent.

Separation and quantitation of linoleic acid oxidation products in mammary gland tissue from mice fed low- and high-fat diets.

We have developed an assay for the isolation and quantitation by gas chromatography-mass spectrometry (GC-MS) of free 9- and 13-hydroxyoctadecadienoic acid (9-HODE, 13-HODE) in the mammary glands of female mice. Internal standards consisting of 18O2-labeled analogs of 9- and 13-HODE are added to pulverized frozen tissue prior to extraction with ethanol. Nonlipid materials are removed in a chloroform/methanol/water step. The remaining lipid material is methylated with ethereal diazomethane, and much of the nonoxygenated fatty acid methyl esters are removed via silica solid-phase extraction. Samples are either further derivatized with bis(trimethylsilyl)trifluoroacetamide to form the trimethylsilyl ethers for quantitative analysis by GC-MS or are analyzed as the methyl esters by chiral high-performance liquid chromatography to determine the enantiomeric distribution of the 9- and 13-HODE. The extraction and quantitation protocol was applied to the analysis of mammary glands for free 9- and 13-HODE from mice fed isocaloric diets containing 20% corn oil, 5% corn oil, or 20% beef tallow. Chiral analysis of the products showed higher production of 13(S)-HODE relative to 13(R)-HODE; the enantiomeric excess is most likely due to enzymatic production of 13-HODE superimposed on a background of autoxidative production of 13(R)- plus 9(S)- and 9(R)-HODE. In addition, the effect of sample handling and storage conditions on the formation of 9- and 13-HODE in the samples was assessed by exposing aliquots of a common pool of rat mammary gland tissue to specified conditions prior to analysis. This methodology will be important during investigations of the contribution of linoleate oxidation products to the enhancement of mammary tumorigenesis by dietary fat.

LAR-PTPase cDNA transfection suppression of tumor growth of neu oncogene-transformed human breast carcinoma cells.

The incidence of amplification of neu oncogene-encoded protein tyrosine kinase in human breast cancer strongly supports the concept that protein tyrosine phosphorylation and dephosphorylation are key regulatory mechanisms in the proliferation, differentiation, and neoplastic transformation of breast epithelial cells. We examined the potential regulatory role of protein tyrosine phosphatases (PTPases) in the maintenance of cellular tyrosine phosphorylation by the introduction of leukocyte common-antigen-related PTPase (LAR-PTPase) cDNA into a tumorigenic human breast carcinoma cell line that overexpressed p185neu protein tyrosine kinase. The transfected human breast carcinoma cells expressed elevated levels of LAR-PTPase as assessed by reverse transcription-polymerase chain reaction and by analysis of LAR-PTPase protein. The LAR-PTPase-transfected human breast carcinoma cells had a significantly (P < 0.01) slower proliferation rate in vitro than control-transfected cells. When LAR-PTPase-transfected cells were inoculated into athymic nude mice, a consistent and significant (P < 0.05) suppression of tumor growth was observed. These results provide evidence that a specific PTPase, LAR-PTPase, can play a suppressive regulatory role in the tumor growth of human breast carcinoma cells that overexpress p185neu protein tyrosine kinase.

Review of the effects of dietary fat on experimental mammary gland tumorigenesis: role of lipid peroxidation.

The purpose of this communication is threefold, that is, (1) to review and critique the studies designed to examine the interrelationship between dietary fat and experimental rodent mammary gland tumorigenesis, (2) to assess the influence of dietary fat on growth of human breast carcinoma transplants in immunodeficient mice, and (3) to examine and discuss the role of products of lipid peroxidation in these tumorigenic processes. It is concluded from this review and critique that the amount and type of dietary fat can significantly influence the development and/or growth of rodent mammary gland tumors and growth of human breast carcinomas in immune deficient mice. Dietary fat can be either stimulatory or inhibitory to these tumorigenic processes, phenomena that could be a function, at least in part, of the generation of products of lipid peroxidation.

Two types of normal human breast epithelial cells derived from reduction mammoplasty: phenotypic characterization and response to SV40 transfection.

A culture method to grow two morphologically distinguishable normal human breast epithelial cell types derived from reduction mammoplasty has been developed. Type I cells were characterized by a more variable cell shape, smooth cell colony boundaries, the expression of epithelial membrane antigen (EMA) and keratin 18 and the non-expression of keratin 14 and alpha 6 integrin. In addition, the Type I cells were growth stimulated by fetal bovine serum (FBS) and were deficient in gap junctional intercellular communication (GJIC). In contrast, Type II cells were characterized by a uniform cell shape, expression of keratin 14 and alpha 6 integrin and the non-expression of EMA and keratin 18. In addition, Type II cells were growth inhibited by FBS and were proficient in GJIC. Type I cells can be induced by cholera toxin to change their morphology to a Type II cell morphology. Hence, Type I cells antigenically resemble luminal epithelial cells, while the Type II cells more closely resemble basal epithelial cells. Type I and Type II cells were transfected with SV40 DNA. Clones with extended lifespans were obtained from both Type I and Type II cells by SV40 transfection. Some (2/9) of the SV40-transfected Type I cell clones became immortal (> 100 cumulative population doubling level), whereas none (0/8) of the SV40-transfected Type II cell clones became immortal. The SV-40-transfected Type I and Type II cell-derived extended life clones and immortal cell lines phenotypically resembled their parental cells with respect to EMA, keratin 14 and keratin 18 expression and GJIC. Each (9/9) of the SV40 transfected Type I cell clones grew in soft agar; none (0/8) of the SV40-transfected Type II cell clones were capable of growing in soft agar. These results provide evidence that normal human breast epithelial cells, derived from reduction mammoplasty, can be separated into two morphologically and antigenically different cell types and that these two different cell types significantly differ in their response to an oncogenic (SV40) stimulus.

Inhibition of gap junctional intercellular communication and malignant transformation of rat liver epithelial cells by neu oncogene.

A retrovirus containing a neu oncogene was introduced into a Fischer F344 rat liver epithelial cell line (WB-F344) to study the effect of the expression of neu oncoprotein on gap junctional intercellular communication (GJIC), the ability to form colonies in soft agar and the ability to form tumors in rat liver by these cells. After viral infection, five different neu-transduced epithelial clones were randomly selected for further analysis. Southern blot analysis of HindIII-digested genomic DNA hybridized with a neu-specific probe indicated that the neu oncogene carried by the retrovirus was integrated into different chromosomal locations in the five different neu-transduced WB cell lines. Using the fluorescence recovery after photobleaching (FRAP) assay, we found that GJIC was significantly reduced in neu-transduced WB clones, compared with control virus-infected and parental WB cells. Western blot analysis of connexin 43 in the neu-transduced cell lines showed altered phosphorylation patterns compared with the normal WB-rat liver cell line. Confocal image analysis of the neu-transduced cells showed that the connexin 43 protein, as detected by fluorescent immunostaining, was localized in the cell nucleus. The neu-transduced WB cell lines also acquired the ability to grow in soft agar. Furthermore, cells from three of the five neu-transduced cell lines, when injected into the liver of Fischer F344 rats through the portal vein, were highly tumorigenic (multiple focal hepatic tumors developed within 2 weeks). Cells derived from the tumor were shown to be G-418 resistant, demonstrating that the tumor was derived from the injected WB-neu cells. The results of this study demonstrate that the expression of the neu oncogene is able to block GJIC and to induce tumorigenicity in the rat liver WB-F344 cell line.

Modulatory influence of camphor on the activities of hepatic carcinogen metabolizing enzymes and the levels of hepatic and extrahepatic reduced glutathione in mice.

The present paper deals with the modulatory influence of camphor on the activities of hepatic phase I and phase II drug metabolising enzymes and the levels of hepatic and extrahepatic reduced glutathione contents in the mouse. Female Swiss albino mice (8-9 weeks old) were treated daily by oral route for 20 days with 50, 150 or 300 mg/kg body weight of camphor dissolved in 0.1 ml of olive oil. Camphor only at the 300 mg/kg body weight dose level caused a significant increase in the activities of cytochrome P450 (P < 0.05), cytochrome b5 (P < 0.05), aryl hydrocarbon hydroxylase (P < 0.05) and glutathione S-transferase (P < 0.05). These modulatory effects were comparable with those induced by 0.75% BHA diet given for 20 days (positive control group). The reduced glutathione level was elevated significantly in liver (P < 0.05) by camphor only at the 300 mg/kg body weight dose level and in liver, lung and stomach (P < 0.05) by BHA.

Inhibition of growth of human breast carcinoma xenografts by energy expenditure via voluntary exercise in athymic mice fed a high-fat diet.

The purpose of this study was to assess the effect of energy expenditure, via voluntary exercise, on growth of xenografts of human breast carcinomas in athymic nude mice. Sedentary and exercising athymic nude mice bearing subcutaneous grafts of MDA-MB231 human breast carcinomas were fed daily a purified high-fat diet at 10% less than ad libitum to ensure an equal quantity of diet (energy) consumption for each sedentary and exercising mouse. The sedentary and exercising mice were housed singly; the exercising mice had, in addition, access to an activity wheel (24 hrs/day). Growth of human breast carcinomas (carcinoma volumes) was evaluated during a five-week periods. Mean running activities of individual mice over the five-week period ranged from < 1 to 7.9 miles/day. Growth of the human breast carcinomas was significantly inversely correlated with the mean number of miles that each mouse ran per day (p < 0.018). Upon separation of these mice into two running groups, i.e., those that averaged 2.7-4.7 miles/day and those that averaged > 4.7 miles/day, carcinoma growth was 83% of sedentary controls in the former group (p = 0.305) and 59% of sedentary controls in the latter group (p = 0.039). These results provide evidence that energy expenditure, via voluntary use of an activity wheel, can reduce significantly the growth of human breast carcinomas maintained in athymic nude mice.

Caffeine and the development of the normal and neoplastic mammary gland.

There has been much interest in the role of dietary factors in the etiology and progression of breast disease. Due to its wide consumption and the many biochemical and physiological effects it exerts, caffeine has been extensively examined in both clinical and experimental animal studies. To date, clinical studies investigating a possible relationship between caffeine consumption and breast disease in humans have yielded inconsistent and inconclusive results. In experimental animal studies utilizing laboratory mice and rats, caffeine has been shown to stimulate mammary gland lobulo-alveolar development and secretion. The development of mammary gland tumors can be either stimulated or suppressed depending upon the animal species and strain, and the stage of tumorigenesis (initiation/promotion) at which caffeine is administered. Many laboratories have proposed that antagonism of the adenosine receptor is the most plausible mechanism to account for the many biological activities of caffeine. However, other mechanisms by which caffeine act cannot be discounted. The significant modifying role of caffeine on normal and neoplastic mammary gland development in experimental animals provides a biological foundation from which to implicate caffeine as a potential modulator of developmental growth of normal, benign, and carcinomatous human breast tissues.

Interrelationship between dietary lipids and calories and experimental mammary gland tumorigenesis.

The purpose of this communication was to review and critique the studies designed to examine the interrelationship between dietary fat and calories in experimental rodent mammary gland tumorigenesis. The results of these studies clearly show that hyperalimentation of fat, either saturated or unsaturated, significantly stimulates this tumorigenic process. This has been demonstrated in an impressive array of carcinogen-induced, transplantable, spontaneous, and metastatic experimental rodent mammary gland tumor systems. The stimulatory effect of high levels of dietary fat appears to act primarily at the promotional stage of this tumorigenic process. Whether the mammary tumor stimulatory effect of high levels of dietary fat is a result of the metabolic activity of the fat per se or is due to an excessive energy (caloric) intake has been examined. Data obtained from the experimental studies that address this issue support the viewpoint that the mammary tumorigenic-enhancing activities of a high fat diet is, at least in part, through a caloric mechanism.

Enhancement by caffeine of mammary gland lobulo-alveolar development in mice: a function of increased corticosterone.

Previously we have reported that the stimulatory effect of caffeine on lobulo-alveolar development in the mammary glands of female Balb/c mice is not due to a direct action of the drug on the mammary gland but appears to be due to a caffeine-induced alteration of a yet to be defined systemic physiological process (VanderPloeg et al., J Environ Pathol Toxicol Oncol 11:177-189, 1992). In the present study, we administered caffeine (via the drinking water, 500 mg/L) to ovariectomized, estrogen- and progesterone-treated Balb/c mice. After 30 days of caffeine treatment, a significant (p < 0.001) enhancement of lobulo-alveolar development in the mammary glands of the hormone-treated mice, compared with hormone treated control mice, was observed. Six blood components, that is, total free fatty acids (FFA), glucose, IGF-1, insulin, prolactin and corticosterone, each known to enhance normal or neoplastic mammary gland growth processes in mice or rats, were quantitatively assessed in the blood of these mice. Of these six blood components, only corticosterone (p < 0.001) increased significantly in the caffeine-treated mice. These results provide evidence that the enhancement of mammary gland lobulo-alveolar development in mice by chronic consumption of caffeine appears to be a result of caffeine-enhanced secretion of corticosterone.

Dietary fish oil inhibits human breast carcinoma growth: a function of increased lipid peroxidation.

Female athymic nude mice were implanted subcutaneously with human breast carcinoma MDA-MB231. Seven to ten days later, the mice were divided into groups and fed a purified diet containing the following types of fat (% of diet): (i) 20% corn oil (CO); (ii) 15% CO:5% fish (menhaden) oil (FO); (iii) 10% CO:10% FO; (iv) 5% CO:15% FO; (v) 1% CO:19% FO; and (vi) 1% CO:19% FO plus antioxidants (alpha-tocopherol acetate, 2000 IU/kg diet and tertiary butyl-hydroquinone, 2% of total fat). The linoleic acid levels (% of diet) of the groups were 12.0, 9.1, 6.2, 3.3, 0.9 and 0.9%, respectively. After 6-8 wk, the carcinomas were assessed for tumor volume (cm3) and assayed for thiobarbituric acid reactive substances (TBARS). Human breast carcinoma growth was suppressed in mice consuming FO diets without antioxidants as compared to mice fed CO; the greater the amount of dietary FO fed, the greater the carcinoma growth suppression (P < 0.05). The addition of antioxidants to the FO diet significantly (P < 0.05) reversed the FO-induced carcinoma growth suppression. Concentrations of TBARS in the human breast carcinomas were increased in all the FO (without antioxidants) fed mice, compared to mice fed CO; the level of increase in TBARS was directly related to the increase in the level of FO fed (P < 0.05). The addition of antioxidants to the FO diet significantly (P < 0.05) reduced the concentration of TBARS in the breast carcinomas.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased expression of specific protein tyrosine phosphatases in human breast epithelial cells neoplastically transformed by the neu oncogene.

Protein tyrosine phosphorylation/dephosphorylation is a fundamental mechanism in the regulation of cell proliferation and neoplastic transformation; this metabolic process is modulated by the opposing activities of protein tyrosine kinases and protein tyrosine phosphatases (PTPases). While the role of protein tyrosine kinases has been examined extensively in human breast tumorigenesis, the role of PTPases in this process is virtually unknown. To address this issue, an activated neu oncogene was introduced into an immortalized nontumorigenic human breast epithelial cell line (184B5). This resulted in a substantial increase in P185neu expression, which led to the formation of progressively growing carcinomas after such cells were inoculated into athymic nude mice. Importantly, a striking increase in the expression of specific PTPases, LAR and PTP1B, was observed in 3 independently neu transformed cell lines and their derived tumors. This elevation was verified at both the mRNA and protein levels. TC-PTP PTPase expression was only slightly increased in these neu transformed cells, and no expression of CD45 PTPase was observed. The level of neu expression, as well as the differential expression between P185neu and LAR/PTP1B, directly correlated with tumorigenicity. Furthermore, rat mammary carcinomas with elevated neu expression (neu-induced) also had sharply elevated LAR-PTPase expression when compared to rat mammary carcinomas with little or no neu expression (7,12-dimethylbenzanthracene induced); the level of expression of LAR PTPase was directly correlated with the level of neu expression. Thus, our results provide the first evidence that, in human breast carcinoma cells and in rat mammary carcinomas that have an induced increase in neu expression, a consistent and substantial increase in the expression of specific PTPases occurs. The relationship between P185neu-protein tyrosine kinase expression and specific PTPase expression may play a critical role in human breast tumorigenesis.

Comparative abilities of athymic nude mice and severe combined immune deficient (SCID) mice to accept transplants of induced rat mammary carcinomas: enhanced transplantation efficiency of those rat mammary carcinomas that have elevated expression of neu oncogene.

Grafts of primary carcinogen (DMBA)-induced mammary carcinomas from Sprague-Dawley rats have a poor transplantation efficiency in athymic nude mice. Further compromising these mice immunologically via whole-body irradiation and/or splenectomy, or the administration of hormonal growth factors (estrogen and progesterone) to these mice, did not significantly alter transplantation efficiency. Use of strains of mice that are more immune-impaired than the athymic nude mouse, i.e., the athymic nude-beige-XID mouse (T-cell and LAK-cell deficient) or mice with severe combined immune deficiency (SCID) (which lack functional T cells and B cells) also failed to improve transplantation efficiency. In contrast, transplantation efficiency was sharply increased when primary neu-induced rat mammary carcinomas from female Sprague-Dawley rats were used. These mammary carcinomas, unlike the DMBA-induced rat mammary carcinomas, have a very high level of expression of neu; transplantation of these tumors to either athymic nude mice or SCID mice was considerably more efficient. Thus, these data provide evidence that enhanced expression of neu confers heightened efficiency in the transplantation of primary rat mammary carcinomas to immune-deficient mice (athymic-nude or SCID). Increased neu expression was a greater determinant than more compromised immune states in the transplantation of these rat mammary carcinomas. This biological characteristic of neu expression in mammary carcinomas provides new, additional insight into the importance of this oncogene in mammary tumorigenic processes and may explain, at least in part, the reported inverse relationship between human breast carcinoma neu expression and patient prognosis.

Suppression of growth by dietary fish oil of human breast carcinomas maintained in three different strains of immune-deficient mice.

It has been reported that high levels of dietary fish (menhaden) oil, compared with corn oil, suppress the growth of MDA-MB231 and MCF-7 human breast carcinomas maintained in female athymic nude (T lymphocyte-deficient) mice. The purpose of this study was to determine whether dietary fish (menhaden) oil, compared with corn oil, can also suppress the growth of these carcinomas when maintained in female beige-XID-athymic nude (T lymphocyte- and NK/LAK cell-deficient) mice and in female severe combined immune-deficient (SCID) mice (total lack of functional T and B lymphocytes). Results clearly show that dietary fish (menhaden) oil can significantly (p < 0.05) suppress the growth of these carcinomas in the beige-XID-athymic nude mouse and the SCID mouse. Such results provide evidence that the growth suppression of MDA-MB231 and MCF-7 human breast carcinomas, induced by dietary fish oil, is not mediated by immune system mechanisms involving T lymphocytes, B lymphocytes, and/or NK/LAK cells.

Lipid peroxidation products are elevated in fish oil diets even in the presence of added antioxidants.

Purified corn and fish oil diets with different types and concentrations of antioxidants were evaluated for oxidation products. In addition, a determination of different organ and carcass oxidation product levels was performed. Peroxide value and thiobarbituric acid assays were performed on the diets immediately after mixing (0 h) and 24, 48 and 72 h after being fed to mice. The AIN-recommended level of antioxidant addition (butylated hydroxytoluene, 0.02 g/100 g oil) and even the addition of 100 times this level (2 g/100 g oil), although decreasing the level of oxidation products, failed to totally prevent oxidative deterioration in diets high in fish oil. Furthermore, other antioxidants added in excess to the fish oil diets also failed to completely suppress oxidative deterioration of the diets and, in addition, when fed daily to mice for a period of 4 wk, caused an accumulation of lipid peroxidation products in certain organs (e.g., heart, skeletal muscle, mammary glands) and in the carcass. These results provide evidence that in the preparation of fish oil diets, the addition of antioxidants at the AIN-recommended level, or even levels substantially higher, does not completely suppress oxidative deterioration of experimental diets.

Caffeine, theophylline, theobromine, and developmental growth of the mouse mammary gland.

The purpose of this study was to determine the comparative activities of three methylxanthines, i.e., 1,3,7-trimethylxanthine (caffeine), 1,3-dimethylxanthine (theophylline), and 3,7-dimethylxanthine (theobromine) on developmental growth of the mammary gland in ovarian-hormone treated, mature nulliparous female Balb/c mice. When caffeine or theophylline was administered daily (via drinking water, 500 mg/L) for 30 days to 17 beta-estradiol/progesterone-treated intact or ovariectomized mice, a significant (p less than 0.05) enhancement of hormone-induced mammary gland lobulo-alveolar differentiation was observed. Caffeine or theophylline thus accelerated and/or intensified mammae lobulo-alveolar differentiation induced by the ovarian steroids. In contrast, theobromine (500 mg/L drinking water) did not significantly modify this developmental process. The stimulatory effect of caffeine and theophylline on mammae development was comparable quantitatively. In an effort to determine whether or not the stimulatory effect of caffeine or theophylline was directly on the mammary gland, small slow-release Elvax-40P pellets containing these methylxanthines were implanted directly into the mammary gland of mice concurrently treated with estrogen and progesterone. No significant stimulatory effect of caffeine or theophylline (or theobromine) was observed. Furthermore, the addition of methylxanthines (caffeine, 100 microM) to the culture media of whole mouse mammary glands (organ cultures) did not enhance lobulo-alveolar differentiation induced by mammotrophic hormones. Thus, while a consistent significant stimulatory effect of caffeine and theophylline on mammary lobulo/alveolar differentiation was observed when the methylxanthines were consumed orally (drinking water), no direct effect of these methylxanthines, when placed directly into the mammary gland or in culture media, on mammae development was observed. These data demonstrate that certain methylxanthines (e.g., caffeine and theophylline) but not others (e.g., theobromine) can significantly enhance mammotrophic hormone-induced mammary lobulo-alveolar differentiation in female Balb/c mice, an effect that appears not to be manifested via a direct action of the methylxanthines on the mammary gland.

Relationship between dietary fat and experimental mammary tumorigenesis: a review and critique.

That dietary fat can significantly affect mammary tumorigenesis in mice and rats has been clearly established. The purpose of this communication is to review and critique this interesting and potentially important relationship. This review focuses on the relationship between the amount and type of dietary fat and the role of calories in rodent mammary tumor development and metastasis. Additionally, the influence of dietary fat on development of human breast carcinoma transplants in immunodeficient mice is examined. The numerous studies cited in this review provide a compelling biological foundation for a potentially important relationship between dietary fat and/or calorie consumption and breast carcinoma development in human populations.