Tobacco cessation outcomes in a cohort of patients attending a chest medicine outpatient clinic in Bangalore city, southern India.

BACKGROUND & OBJECTIVES: Nicotine dependence is a widely prevalent and harmful chronic addictive disorder. Quitting tobacco use is however, uncommon in India. We present long-term treatment outcomes of out-patient, tobacco cessation treatments from a specialty clinic setting in southern India. METHODS: Patients seen in a tobacco cessation clinic were characterized for tobacco use, nicotine dependence and motivation for quitting and offered pharmacologic/non-pharmacologic treatment. They were subsequently contacted telephonically at a mean (±standard deviation) of 24 (±9.1) months to assess tobacco cessation outcome defined as 'point prevalence of 1-month abstinence' by self-reporting. RESULTS: The mean age of participants was 48.0 ±14.0 yr. Tobacco use distribution was: beedis only (22%), cigarettes only (49%), beedis and cigarettes (18%), chewing only (2%), and smoking and chewing (9%). Two-thirds had high level of nicotine dependence. Of the 189 patients enrolled, only 15 per cent attended follow up clinics. Only 106 (56%) patients were successfully contacted telephonically and 83 (44%) were lost to follow up. Self-reported point prevalence abstinence was 5 per cent by 'intent-to-treat' analysis and 10 per cent by 'responder' analysis. Two clinical parameters - high level of nicotine dependence [estimated by the heaviness of smoking index (HSI)] and the absence of vascular or other chronic disease were found to be associated with successful quitting; these were however, not significant on multivariate analysis. INTERPRETATION & CONCLUSIONS: Our study has identified low quit-rates in a cohort of patients attending a hospital-based tobacco cessation clinic. In the absence of clear-cut predictors of cessation with low quit-rates, there should be continued efforts to improve cessation outcomes and identify predictors for action.

Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer.

Upper body obesity and the related metabolic disorder type 2 diabetes have been identified as risk factors for breast cancer, and associated with late-stage disease and a poor prognosis. Components of the metabolic syndrome, including visceral adiposity, insulin resistance, hyperglycemia and hyperinsulinemia, with or without clinically manifest diabetes mellitus, low serum high-density lipoprotein cholesterol and hypertension have all been related to increased breast cancer risk. The biochemical mechanisms include extraglandular oestrogen production, reduced sex hormone-binding globulin with consequent elevation of the bioactive plasma free oestradiol and increased insulin biosynthesis, all of which exert mitogenic effects on both untransformed and neoplastic breast epithelial cells. Obesity, type 2 diabetes and the metabolic syndrome also have in common an increased production of leptin and a decreased production of adiponectin by adipose tissue, with consequent elevations and reductions, respectively, in the circulating levels of these two adipokines. These changes in plasma leptin and adiponectin, acting through endocrine and paracrine mechanisms, have been associated in several studies with an increase in breast cancer risk and, perhaps, to more aggressive tumours; studies in vitro showed that leptin stimulates, and adiponectin inhibits, tumour cell proliferation and the microvessel angiogenesis which is essential for breast cancer development and progression.

Obesity, adipocytokines, and insulin resistance in breast cancer.

The adipocytokines are biologically active polypeptides that are produced either exclusively or substantially by the adipocytes, and act by endocrine, paracrine, and autocrine mechanisms. Most have been associated with obesity, hyperinsulinaemia, type 2 diabetes, and chronic vascular disease; in addition, six adipocytokines--vascular endothelial growth factor, hepatocyte growth factor, leptin, tumour necrosis factor-alpha, heparin-binding epidermal growth factor-like growth factor, and interleukin-6--promote angiogenesis while one, adiponectin, is inhibitory. Obesity and insulin resistance have both been identified as risk factors for breast cancer and are associated with late-stage disease and poor prognosis. Angiogenesis is essential for breast cancer development and progression, and so it is plausible that obesity-related increases in adipocytokine production and a reduction in adiponectin may adversely affect breast cancer outcome by their angiogenesis-related activities. There is also experimental evidence that some adipocytokines can act directly on breast cancer cells to stimulate their proliferation and invasive capacity. Thus, adipocytokines may provide a biological mechanism by which obesity and insulin resistance are causally associated with breast cancer risk and poor prognosis. Both experimental and clinical studies are needed to develop this concept, and particularly in oestrogen-independent breast cancers where preventive and therapeutic options are limited.

Loss of expression of protein kinase C beta is a common phenomenon in human malignant melanoma: a result of transformation or differentiation?

As with most cancers, the aetiology of human cutaneous melanoma is likely to be multifactorial and to include the accumulation of irreversible alterations in an unknown number of genes. Elucidating this molecular progression necessitates both the identification of genetic perturbations at each clinically relevant stage, and the assessment of their impact on the normal melanocyte. The observation that the epidermal melanocyte, in contrast to metastatic melanoma cells, requires activation of the protein kinase C (PKC) pathway to facilitate growth in vitro indicates that one or more isoforms (or substrates) of this large and complex family of proteins are among those that undergo alteration during the development of malignant melanoma. Consequently, a number of studies have investigated the expression of various PKC family members in both melanocyte and melanoma cell lines, without a consensus of opinion as to which isoforms are of biological significance in melanoma development and progression. The present study involved a comprehensive evaluation of the PKC profile in normal melanocytes and in 16 metastatic melanoma cell lines. The results show that the major difference in isoform expression between epidermal melanocytes and melanoma cells is the loss of PKCbeta protein expression in 90% of melanoma cell lines. Examination of PKCbeta in benign and malignant melanocytic lesions revealed that this protein is either downregulated or absent in both naevi and metastatic melanomas. We conjecture that, although the loss of PKCbeta expression is a common phenomenon in malignant melanocytes, it may be related more to a normal process of melanocytic differentiation than to malignant transformation.

Tumor biology and prognosis in black breast cancer patients: a review.

American black women have a risk of developing breast cancer lower than that of American white women. but they have a worse prognosis when they do develop the disease. A major factor responsible for this discrepancy is a relatively high poverty level in the black population, with the consequent likelihood of delayed diagnosis and presentation with more advanced disease. However, breast cancer in black women also occurs at a younger age, more often is estrogen receptor-negative, and more frequently exhibits aggressive biological behavior as judged by histopathologic grade, high tumor cell proliferation rate, and altered p53 expression. Obesity, known to be associated with a poor prognosis primarily as a consequence of increased estrogen production and bioavailability, is more common in black than in white breast cancer patients. An additional factor may be an earlier age at first completed pregnancy for black women, which is associated with a reduced breast cancer risk but also a poorer prognosis. Both the epidemiologic features and the tumor biology of breast cancer in black women serve to stress the particular importance of developing effective, specifically tailored strategies for early diagnosis in this ethnic group.

Cell cycle arrest and apoptosis of melanoma cells by docosahexaenoic acid: association with decreased pRb phosphorylation.

The incidence of cutaneous malignant melanoma is undergoing a dramatic increase in persons with light-color skin in all parts of the world. The prognosis for individuals with advanced disease is dismal due to the lack of effective treatment options. Thus, there is a need for new approaches to control tumor progression. Epidemiological, experimental, and mechanistic data implicate omega-6 polyunsaturated fatty acids (PUFAs) as stimulators and long-chain omega-3 PUFAs as inhibitors of development and progression of a range of human cancers, including melanoma. The aim of this study was to assess the mechanisms by which docosahexaenoic acid (DHA), an omega-3 PUFA, affects human melanoma cells. Exponentially growing melanoma cell lines were exposed in vitro to DHA and then assessed for (a) inhibition of cell growth; (b) expression of cyclins and cyclin-dependent kinase inhibitors in individual cells by flow cytometry and immunocytochemistry using specific monoclonal antibodies to cyclin D1, cyclin E, p21WAF1/CIP1, or p27(KIP1); and (c) expression of total pRb(T) independent of phosphorylation state and hypophosphorylated pRb(P-) in fixed cells by flow cytometry and immunocytochemistry using specific monoclonal antibodies to pRb(T) or pRb(P-), respectively. After treatment with increasing concentrations of DHA, cell growth in a majority of melanoma cell lines (7 of 12) was inhibited, whereas in 5 of 12 cell lines, cell growth was minimally affected. Two melanoma cell lines were examined in detail, one resistant (SK-Mel-29) and one sensitive (SK-Mel-110) to the inhibitory activity of DHA. SK-Mel-29 cells were unaffected by treatment with up to 2 microg/ml DHA whether grown in the absence or presence of 1% fetal bovine serum (FBS). No appreciable change was observed in cell growth, cell cycle distribution, the status of pRb phosphorylation, cyclin D1 expression, or the levels of the cyclin-dependent kinase inhibitors p21 and p27. In contrast, SK-Mel-110 cell growth was inhibited by DHA with the cells accumulating either in G1 or S phase: 0% in SK-Mel-29 versus 13.3 or 41.2% in SK-Mel-110 in the absence or presence of FBS, respectively. In the absence of serum, considerable death occurred by apoptosis. In addition, DHA treatment resulted in increasing numbers of SK-Mel-110 cells (from 12 to >40%) expressing hypophosphorylated pRb, whereas the levels of cyclin D1 and p21 changed little. Expression of p27 in these cells increased >2.5 times when grown in the absence of FBS but not in the presence of 1% FBS. Thus, we show for the first time that DHA inhibits the growth of cultured metastatic melanoma cells. Furthermore, growth inhibition correlates with a quantitative increase in hypophosphorylated pRb in the representative sensitive melanoma cell line SK-Mel-110. Although multiple factors influence pRb phosphorylation, it appears that both cyclin D1 and p21 expression do not change in the presence of DHA, although p27 was strikingly increased in SK-Mel-110 cells in the absence of FBS. The fact that pRb became hypophosphorylated after exposure to DHA suggests a cross-talk mechanism between fatty acid metabolism and the pRb pathway. Determining the mechanism by which PUFAs can inhibit melanoma growth will be an important first step in the rational use of PUFAs as antitumor agents.

Regulation of tumor angiogenesis by dietary fatty acids and eicosanoids.

Angiogenesis is a prerequisite for tumor growth and metastasis. Vascular endothelial cell proliferation, migration, and capillary formation are stimulated by angiogenic growth factors, which include the proteins vascular endothelial growth factor, basic fibroblast growth factor, and transforming growth factor-beta, and eicosanoids synthesized from n-6 fatty acids. Clinical studies have shown that angiogenesis in solid tumors relates to a poor prognosis and, in premalignant lesions, indicates potential for cancerous transformation. High-fat, n-6 fatty acid-rich diets were associated with a relatively poor prognosis in breast cancer patients; in a nude mouse model the same diet enhanced breast cancer progression, whereas n-3 fatty acids exerted suppressive effects that were associated with impaired angiogenesis. Lipoxygenase and cyclooxygenase products of n-6 fatty acid metabolism are angiogenic in in vitro assays. This activity is blocked by pharmacological inhibitors of eicosanoid biosynthesis, and one, indomethacin, suppressed n-6 fatty acid-stimulated murine mammary carcinoma growth and metastasis and tumor vascularization. Review of the experimental data suggests that selective inhibitors of eicosanoid-synthesizing enzymes and dietary intervention with n-3 fatty acids merit clinical evaluation as adjuvant therapy and chemopreventive agents.

Omega-3 fatty acids as cancer chemopreventive agents.

There is both epidemiologic and experimental evidence that the long-chain omega-3 fatty acids (FAs), which occur at high levels in some fish oils, exert protective effects against some common cancers, notably those of breast, colon, and, perhaps, prostate. Multiple mechanisms are involved in this chemopreventive activity, including suppression of neoplastic transformation, cell growth inhibition and enhanced apoptosis, and antiangiogenicity; however, a common feature of most of these biological effects is the inhibition of eicosanoid production from omega-6 FA precursors. Several of the known risk factors for breast, and colon cancer may be favorably modified by dietary omega-3 FA supplementation, and the implementation of clinical chemoprevention trials is now feasible.

Antiangiogenicity of docosahexaenoic acid and its role in the suppression of breast cancer cell growth in nude mice.

The addition of the omega-3 fatty acid (n-3 FA) docosahexaenoic acid (DHA), 4%, to a 20% (wt/wt) fat diet containing 4% linoleic acid (LA, n-6 FA) partially suppressed the growth of the MDA-MB-231 human breast cancer cell line as solid tumors in athymic nude mice. This reduced tumor growth was associated with significant inhibition of cell proliferation, as indicated by diminished Ki-67 nuclear proliferation marker expression, and an increase in TUNEL positive (apoptotic) cells (both p<0.001). The microvessel counts were also reduced in tumors from the DHA-supplemented dietary group of mice (p<0.001), and this suppression of angiogenesis was positively correlated with loss of Ki-67 expression. Tumor vascular endothelial cell growth factor (VEGF) concentrations were not reduced in the DHA-fed mice. It is postulated that the antiangiogenicity of DHA in this breast cancer model is related to our demonstrated inhibition of LA-derived prostaglandin E2, 12-hydroxyeicosatetraenoic acid (12-HETE) and 15-HETE synthesis, reducing the paracrine stimulation by these known angiogenic eicosanoids on microvessel endothelial cells.

The association between a mutated ras gene and cyclooxygenase-2 expression in human breast cancer cell lines.

Cyclooxygenase (COX) is rate-limiting for arachidonic acid metabolism to the prostanoid family of eicosanoids. Some human breast cancers, notably those which are estrogen receptor (ER)-negative with high metastatic potential, produce high levels of prostaglandin E2 (PGE2). In some cell types, expression of the inducible COX-2 isoform occurred in association with a ras gene mutation. We determined COX-1 and COX-2 expression, and the corresponding PGE2 secretions, in 4 ER-negative human breast cancer cell lines, the MCF10A breast epithelial cell line, and the same non-cancerous line transfected with a mutated ras gene. The highly invasive MDA-MB-231 and Hs578T cancer cell lines, which possess a mutated Ki-ras and H-ras, respectively, expressed constitutive and inducible COX-2, and produced high PGE2 levels; the less invasive MDA-MB-435 and SK-BR-3 lines, without a mutated ras, possessed only low levels of COX-2, and secreted correspondingly low PGE2 levels. Similarly, the ras transfectant, but not parental MCF10A cells, expressed inducible COX-2. Chemosuppression with a selective COX-2 inhibitor may be effective only in that minority of breast cancers which have a mutated ras gene.

Effects of reduced dietary linoleic acid intake, alone or combined with an algal source of docosahexaenoic acid, on MDA-MB-231 breast cancer cell growth and apoptosis in nude mice.

Diets rich in linoleic acid (LA), an n-6 fatty acid, stimulate the progression of human breast cancer cell solid tumors in athymic nude mice, whereas docosahexaenoic acid (DHA) and eicosapentaenoic acid, long-chain n-3 fatty acids, exert suppressive effects. In the present study we used a novel source of DHA, in triglyceride form, to determine the effects of feeding low levels of the fatty acid on the growth of MDA-MB-231 cells injected into the thoracic mammary fat pads of female nude mice. Four different isocaloric diets were used, all of which provided 20% (wt/wt) total fat. The control diets contained 8% (20 mice) or 4% (50 mice) LA; the n-3 fatty acid-supplemented groups of 50 mice were fed 4% LA-containing diets plus 2% or 4% DHA. The tumor growth rates were reduced significantly in mice fed the 4% LA compared with the 8% LA diet; the addition of 4% DHA to the 4% LA-containing diet produced a further reduction in tumor growth rate (p < or = 0.003 at and after Week 6). The final tumor weights were also reduced in the DHA-fed mice compared with the 8% LA dietary group (2% DHA, p = 0.02; 4% DHA, p = 0.01) and in the 4% DHA-fed mice compared with the 4% LA control group (p = 0.02); a similar trend for mice fed the lower level of DHA did not achieve statistical significance. Tumor prostaglandin E2 concentrations were reduced by feeding the lower LA level; further dose-dependent decreases occurred in the DHA dietary groups and were accompanied by reduced levels of 12- and 15-hydroxyeicosatetraenoic acids. These changes in eicosanoid biosynthesis may have been responsible for the observed decreases in cell proliferation, indicated by suppressed Ki-67 expression, and increases in apoptotic activity, as reflected in TdT-mediated dUTP nick end labeling immunohistochemical staining.

Influence of dietary linoleic acid on experimental human breast cancer cell metastasis in athymic nude mice.

The effects of linoleic acid (LA), an omega-6 fatty acid precursor for prostaglandin biosynthesis, on the later stages of human breast cancer cell metastasis were studied by the intravenous injection of tumor cells into nude mice (). MDA-MB-435 cells were grown as solid tumors in donor mice fed a 12% or 2% LA-containing diet. These cells were harvested, and injected via a tail vein into recipient mice also fed a 12% LA (Group 1) or 2% LA (Group 2) diet. Other groups were fed 12% LA (Group 3) or 2% LA (Group 4), but injected with the cells grown in vitro in a low-LA culture medium. At necropsy 8 weeks later, the incidence of metastatic lung nodules was higher in Group 1 high LA donor/high LA recipient mice (p<0.001), and, to a lesser degree, Group 2 low LA donor/low LA recipient mice (p<0.05) compared with Groups 3 or 4. The extent of metastasis was significantly higher in Group 1 compared with any of the other groups, including metastasis to the ovaries, which occurred in 27% of the Group 1 mice. These findings show that LA, most likely by increased synthesis of cyclooxygenase products, stimulates metastasis, at least in part, by direct effects on the tumor cells, rather than on potential metastatic sites in the host.

Angiogenesis in two human prostate cancer cell lines with differing metastatic potential when growing as solid tumors in nude mice.

PURPOSE: Angiogenesis, typically a feature of aggressive tumors, is frequently associated with increased vascular endothelial growth factor (VEGF) production. Here, angiogenesis and angiogenic growth factor expression were assessed in two human prostate cancer cell models with differing metastatic potential. METHOD: Prostatic tumors were obtained by injecting either highly metastatic PC-3M cells or poorly metastatic DU145 cells into the surgically exposed prostate glands of nude mice. Angiogenesis was evaluated by immunohistochemical staining, and tumor VEGF, transforming growth factors-beta (TGF-beta1 and TGF-beta2), and basic fibroblast growth factor (bFGF) levels were determined by immunoassays (ELISAs). VEGF isoforms were detected by Western blotting in both solid tumor extracts, and in culture medium conditioned by the same cell lines (CM). RESULTS: Angiogenesis was much more evident in PC-3M tumors (vessel counts: PC-3M tumors 360 +/- 42, DU145 tumors 156 +/- 25; p = 0.003), but ELISA-determined VEGF levels were approximately 3-fold higher in both DU145 cell tumors, and in DU145 cell CM. However, Western blotting showed that PC-3M tumors, but not CM, contained VEGF isoforms with molecular weights of 43 and 57 kDa. TGF-beta2, but not TGF-beta1 concentrations were higher in DU145 cell tumors (p < 0.001); bFGF levels were higher in the PC-3M cell tumors (p < 0.05). CONCLUSIONS: When growing in nude mouse prostate glands, the PC-3M cell line provides a model for the angiogenic activity associated with aggressive prostate cancer. This is accompanied by the expression of immunoreactive VEGF which is not detected by an ELISA antibody raised against the conventional VEGF165, but appears on Western blots as what may prove to be novel high molecular weight species. Observed differences in TGF-beta1 and -beta2, and bFGF expression, may also be associated with an angiogenic phenotype.

Protein kinase C and its isoforms in human breast cancer cells: relationship to the invasive phenotype.

Total protein kinase C (PKC) activity and the expression of 9 isoforms were determined in the estrogen receptor (ER) positive MCF-7 human breast cancer cell line, this line transfected to overexpress either PKC-á or erbB2, and in 3 ER negative breast cancer cell lines. Relationships were sought between PKC and the expression of E-cadherin, alpha-catenin, and vimentin, and urokinase-type plasminogen activator (uPA). In general, PKC enzymic activity and the conventional isoforms PKC-alpha and -gamma were higher in the ER negative, compared with the ER positive, cell lines. Over-expression of PKC-alpha by MCF-7 cells, with ER loss, was associated with the emergence of PKC- expression and a relatively high level of PKC-gamma, features typical of cells with increased proliferation rates; there was also a loss of PKC-delta, consistent with acquisition of the metastatic phenotype. Transfection to overexpress erbB2, with ER retention and slowed growth, produced a decrease in PKC-alpha and -gamma. Vimentin was expressed by the ER negative MDA-MB-231, MDA-MB-435 and PKC-alpha-transfected MCF-7 cells; they also showed loss of E-cadherin and, apart from MDA-MB-435 cells, high levels of uPA secretion. The ER negative SKBr-3 cell line was exceptional in that it had relatively low total PKC activity, low PKC-alpha and -gamma expression and no emergence of vimentin despite loss of E-cadherin expression. Compared with the other two ER negative cell lines, both the SKBr-3 and MDA-MB-435 cells had low PKC activity and uPA secretion. These results are consistent with the involvement of PKC, and notably the conventional isoforms, in the development of the metastatic phenotype, and specifically with the loss of E-cadherin and acquisition of vimentin expression, and the enhanced production of uPA.

Enhanced angiogenesis and growth of 12-lipoxygenase gene-transfected MCF-7 human breast cancer cells in athymic nude mice.

Transfection of the estrogen-dependent and poorly invasive MCF-7 human breast cancer cell line so that it stably overexpressed 12-lipoxygenase and secreted high levels of 12-hydroxyeicosatetraenoic acid when cultured with arachidonate resulted in rapid growth in athymic nude mice when compared with the parental line. This enhanced acquisition of tumor mass was a result of both increased cell proliferation and reduced apoptotic cell death and was accompanied by high angiogenic activity.

Effects of dietary fatty acids on breast and prostate cancers: evidence from in vitro experiments and animal studies.

Linoleic acid, an n-6 polyunsaturated fatty acid, is essential for normal mammary tissue development, at least in part because it provides the metabolic precursor required for the biosynthesis of key eicosanoids. A similar requirement applies to the growth of estrogen-independent but apparently not to estrogen-dependent rodent mammary and human breast carcinoma cells in vitro. By way of lipoxygenase products, n-6 fatty acids also regulate expression of the invasive phenotype. High-fat, linoleic acid-rich diets promote chemically induced rat mammary carcinogenesis, virally induced mouse mammary tumor development, and the growth and metastasis of estrogen-independent human breast cancer cells in athymic nude mice. In contrast, saturated fatty acids have no discernible effects on mammary carcinogenesis or progression. Most mechanistic studies have focused on the cyclooxygenase and lipoxygenase products of n-6 fatty acid metabolism, and support is accumulating for interactions between these eicosanoids and growth factors and oncogenes. The investigation of dietary fatty acids in prostate cancer is at an early stage and has been handicapped by a lack of satisfactory animal models. However, there are indications that the n-6 fatty acids perform functions in experimental prostate cancer progression similar to those described for breast cancer.

Dietary fatty acids and cancer.

Results from epidemiologic studies are controversial with respect to the relation between total dietary fat consumption and breast cancer risk; there is more general agreement that a high-fat diet is associated with aggressive prostate cancer. Recent epidemiologic investigations and laboratory experimentation with animal models suggest that relatively high intakes of long-chain n-3 fatty acids, and n-9 fatty acids present in olive oil, reduce breast cancer risk by mechanisms that may involve modification of the biosynthesis of eicosanoids from n-6 polyunsaturated fatty acids. Although there is only limited support for the hypothesis that total fat intake affects breast cancer risk, there is experimental evidence that n-6 fatty acids, again via eicosanoid production, may enhance breast cancer invasion and metastasis; n-3 fatty acids may exert a suppressive effect. Although studies of prostate cancer are less advanced, the indication is that a high fat intake promotes the emergence of the metastatic phenotype; further research is required to establish the roles of the various classes of fatty acids but it does appear that the long-chain n-3 fatty acids may also retard prostate cancer progression.

Effects of diet supplementation with wheat bran on serum estrogen levels in the follicular and luteal phases of the menstrual cycle.

There is both epidemiologic and experimental support for the hypothesis that a high-fiber diet can reduce breast cancer risk; this may be due, at least in part, to a reduction in circulating estrogens. This study examined the effects of three levels of wheat bran supplementation (5, 10, and 20 g/d for 2 mo) on the major serum estrogens during both the luteal and follicular phases of the menstrual cycle. The 10- and 20-g supplements, which increased the total dietary fiber intakes to approximately 20 and 32 g/d, respectively, resulted in significant decreases in the luteal serum estrone (P < 0.05 and < 0.02, respectively). The serum estradiol was significantly reduced in the 10-g wheat bran group after 2 mo (P < 0.05); the 20-g supplemented group showed a significant decrease in estradiol at 1 mo (P < 0.02), but not at 2 mo. No changes occurred in the estrone sulfate concentrations. During the follicular phase, the 10-g wheat bran group exhibited a significant reduction in the serum estrone (P < 0.02). Only the serum estrone sulfate showed any reduction with the 20-g supplement, and this just failed to achieve significance (P = 0.07). Serum sex hormone-binding globulin levels were unaffected by wheat bran. When of long duration, these effects may be sufficient to favorably influence breast cancer risk in Western women.

Effects of dietary menhaden oil, soy, and a cyclooxygenase inhibitor on human breast cancer cell growth and metastasis in nude mice.

The purpose of Study 1 was to examine the effect of dietary soy on the progression of MDA-MB-435 human breast cancer cell solid tumors in nude mice. When toasted soy chips were fed at levels of 5%, 10%, or 20% (wt/wt) in a high-fat, linoleic acid-rich diet for 12 weeks, there was a trend for larger mammary fat pad tumors to occur with increasing soy intake. However, compared with the controls the severity of macroscopic lung metastasis was reduced significantly in the groups fed 10% and 20% soy. Study 2 compared the effects of diets containing 23% corn oil (CO), 18% menhaden oil (MO) + 5% CO, 18% MO + 5% CO + 10% soy chips, and MO or soy-supplemented diets + indomethacin treatment in the same animal model. Feeding the 18% MO diet without soy or indomethacin reduced primary tumor growth; statistically significant effects were not observed in any of the other groups. All three of the groups with MO supplementation showed a reduction in the occurrence and severity of macroscopic lung metastases, together with the expected decreases in tumor prostaglandin E levels. These effects were most pronounced when MO was combined with indomethacin treatment. When indomethacin was given with dietary soy, the previously reported suppressive effect of the cyclooxygenase inhibitor on MDA-MB-435 cell tumor progression was lost, despite reductions in tumor prostaglandin E concentrations.