transforming-growth-factor-alpha and Obesity

Obesity is a risk factor for postmenopausal breast cancer and is associated with shortened mammary tumor (MT) latency in MMTV-TGF-alpha mice with dietary-induced obesity. One link between obesity and breast cancer is the adipokine, leptin. Here, the focus is on diet-induced obesity and MT and mammary fat pad (MFP) leptin and apoptotic signaling proteins.. MMTV-TGF-alpha mice were fed low-fat or high-fat diets from 10 to 85 weeks of age. High-Fat mice were divided into Obesity-Prone and Obesity-Resistant groups based on final body weights. Mice were followed to assess MT development and obtain serum, MFP, and MT.. Incidence of palpable MTs was significantly different: Obesity-Prone > Obesity-Resistant > Low-Fat. Serum leptin was significantly higher in Obesity-Prone compared with Obesity-Resistant and Low-Fat mice. Low-Fat mice had higher MFP and MT ObRb (leptin receptor) protein and Jak2 (Janus kinase 2) protein and mRNA levels in comparison with High-Fat mice regardless of body weight. Leptin (mRNA) and pSTAT3 (phosphorylated signal transducer and activator of transcription 3) (mRNA and protein) also were higher in MTs from Low-Fat versus High-Fat mice. Expression of MT and MFP pro-apoptotic proteins was higher in Low-Fat versus High-Fat mice.. These results confirm a connection between body weight and MT development and between body weight and serum leptin levels. However, diet impacts MT and MFP leptin and apoptosis signaling proteins independently of body weight.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Blotting, Western; Body Weight; Densitometry; Dietary Fats; Female; Janus Kinase 2; Leptin; Mammary Neoplasms, Experimental; Mice; Obesity; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Transforming Growth Factor alpha

Being overweight is a risk factor for postmenopausal breast cancer and is associated with an increased incidence and shortened latency of spontaneous and chemically induced mammary tumors in rodents. However, leptin-deficient obese Lep(ob)Lep(ob) female mice have reduced incidences of spontaneous and oncogene-induced mammary tumors. Of interest, leptin enhances the proliferation of human breast cancer cell lines in which leptin receptors are expressed, which suggests that leptin signaling plays a role in tumor development. We evaluated oncogene-induced mammary tumor development in obese MMTV-TGF-alpha/Lepr(db)Lepr(db) mice that exhibit a defect in OB-Rb, which is considered to be the major signaling isoform of the leptin receptor. Lepr and MMTV-TGF-alpha mice were crossed, and the offspring were genotyped for oncogene expression and the determination of Lepr status. Lean MMTV-TGF-alpha/Lepr(+)Lepr(+) (homozygous) and MMTV-TGF-alpha/Lepr(+)Lepr(db) (heterozygous) mice and obese MMTV-TGF-alpha/Lepr(db)Lepr(db) mice were monitored until age 104 weeks. Body weights of MMTV-TGF-alpha/ Lepr(db)Lepr(db) mice were significantly heavier than those of the lean groups. No mammary tumors were detected in MMTV-TGF-alpha/Lepr(db)Lepr(db) mice, whereas the incidence of mammary tumors in MMTV-TGF-alpha/Lepr(+)Lepr(+) and MMTV-TGF-alpha/ Lepr(+)Lepr(db) mice was 69% and 82%, respectively. Examination of mammary tissue whole mounts indicated an absence of duct formation and branching for MMTV-TGF-alpha/Lepr(db)Lepr(db) mice. Both age at mammary tumor detection and tumor burden (tumors/mouse and tumor weights) were similar for the lean genotypes. Serum leptin levels of MMTV-TGF-alpha/Lepr(db)Lepr(db) mice were 12-20-fold higher than levels of lean mice. Thus, despite elevated serum leptin levels, leptin receptor-deficient MMTV-TGF-alpha/Lepr(db)Lepr(db) mice do not develop mammary tumors. This study provides additional evidence that leptin and its cognate receptor may be involved in mammary tumorigenesis.

Topics: Animals; Body Weight; Disease Models, Animal; Female; Leptin; Mammary Neoplasms, Experimental; Mammary Tumor Virus, Mouse; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Obesity; Oncogenes; Receptors, Cell Surface; Receptors, Leptin; Survival Analysis; Transforming Growth Factor alpha

Obesity is a risk factor for postmenopausal breast cancer and is associated with shortened latency and/or increased mammary tumor (MT) incidence in animals. Elevated body weight is usually associated with hormone-responsive tumors. In agreement with these data we previously showed that latency of hormone-responsive MTs in MMTV-TGF-alpha mice with diet-induced obesity was significantly shortened. Here, we used the same protocol to determine the impact of diet-induced obesity on estrogen receptor-negative MT development in MMTV-neu (strain 202) mice. Mice were fed a low-fat diet (n=20) or a high-fat diet (n=54) from 10 wk of age. Body weight at 19 wk of age was used to assign high-fat mice to obesity-prone, overweight, and obesity-resistant groups. Mice were euthanized due to MT size or at 85 wk of age. Final body weights of obesity-prone mice were heaviest, and those of obesity-resistant and low-fat groups were similar. Fat pad weights were heaviest in obesity-prone mice followed by overweight and obesity-resistant groups, and lightest in low-fat mice. Serum IGF-I levels were similar for low-fat and high-fat mice, whereas leptin was higher in high-fat mice (P <0.0001). MT latency, incidence, metastasis, and burden were similar for all groups. These findings support that obesity is not a risk factor for development of estrogen-negative breast cancer.

Topics: Adipose Tissue; Animals; Diet; Energy Intake; Female; Genes, erbB-2; Insulin-Like Growth Factor I; Leptin; Mammary Neoplasms, Experimental; Mammary Tumor Virus, Mouse; Mice; Obesity; Transforming Growth Factor alpha

Elevated body weight is a risk factor for postmenopausal breast cancer and is associated with increased incidence of spontaneous and chemically induced mammary tumors (MTs) in rodents. In this study, genetically obese Lep(ob)Lep(ob) female mice that overexpress human TGF-alpha (transforming growth factor-alpha) were used to assess the role of body weight on oncogene-induced MT development in comparison to lean counterparts. MMTV (mouse mammary tumor virus)-TGF-alpha and Lep strain mice were crossed to produce TGF-alpha/Lep(+)Lep(+) (homozygous lean), TGF-alpha/Lep(+)Lep(ob) (heterozygous lean) and TGF-alpha/Lep(ob)Lep(ob) (homozygous obese) genotypes. Body weights were determined weekly and mice palpated for the presence of MTs until 104 weeks of age. Despite their significantly higher body weight, obese TGF-alpha/Lep(ob)Lep(ob) mice failed to develop MTs. MTs were detected between 48 and 104 weeks of age for 26/39 TGF-alpha/Lep(+)Lep(ob) mice and for 19/38 TGF-alpha/Lep(+)Lep(+) mice between 67 and 104 weeks of age. Although MT incidence was not statistically different between the lean groups, age of MT detection tended to be younger for TGF-alpha/Lep(+)Lep(ob) mice (p < 0.09). There were significant effects of both genotype and MTs on final body weight, that is, TGF-alpha/Lep(+)Lep(ob) mice weighed more than homozygous lean mice, and mice with MTs weighed more than those without MTs. TGF-alpha/Lep(ob)Lep(ob) mice are not a good model to evaluate the effect of body weight on MT development possibly due to leptin deficiency. However, the finding that increased body weight is associated with increased oncogene-induced MT development within the normal weight range provides experimental support for the role of body weight in breast cancer.

Topics: Animals; Body Weight; Disease Models, Animal; DNA Primers; Female; Leptin; Mammary Neoplasms, Experimental; Mammary Tumor Virus, Mouse; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Polymerase Chain Reaction; Survival Analysis; Transforming Growth Factor alpha

Topics: Chromosomes, Human, Pair 2; Diabetes Mellitus, Type 2; DNA Primers; Gene Library; Hearing Loss, Sensorineural; Humans; Kidney Diseases; Obesity; Retinitis Pigmentosa; Syndrome; Transforming Growth Factor alpha

Tumor necrosis factor-alpha (TNF-alpha) is chronically elevated in the adipose tissue from obese humans and mice. This increase in TNF-alpha contributes to the insulin resistance, elevated plasminogen activator inhibitor-1 (PAI-1) levels, and cardiovascular complications associated with obesity and noninsulin-dependent diabetes (NIDDM). PAI-1 gene expression in adipose tissue is also stimulated by transforming growth factor-beta (TGF-beta). Experiments were performed to determine whether TGF-beta is regulated by TNF-alpha and elevated in obesity.. The concentration of TGF-beta and PAI-1 mRNA in murine adipose tissue and cultured 3T3-L1 adipocytes was determined by quantitative reverse transcription polymerase chain reaction (RT-PCR), and the cellular localization of these molecules was evaluated using in situ hybridization and cell fractionation. Total TGF-beta protein was determined by employing an ELISA assay.. TGF-beta mRNA and protein were increased in the adipose tissue from two different strains of genetically obese mice (i.e., ob/ob and db/db), compared with their lean counterparts. This increase in TGF-beta may result from TNF-alpha since TNF-alpha increased TGF-beta mRNA expression in the adipose tissue of lean mice and stimulated TGF-beta production by cultured adipocytes. Administration of TGF-beta increased PAI-1 antigen in the plasma and PAI-1 mRNA in the adipocytes of lean mice, and enhanced the rate of PAI-1 synthesis by adipocytes in vitro.. TNF-alpha contributes to the elevated TGF-beta expression demonstrated in the adipose tissue of obese mice. A potential role for TGF-beta in the increased PAI-1 and vascular pathologies associated with obesity/NIDDM is suggested.

Topics: 3T3 Cells; Adipose Tissue; Animals; Cell Fractionation; Gene Expression Regulation; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Plasminogen Activator Inhibitor 1; RNA, Messenger; Transforming Growth Factor alpha; Transforming Growth Factor beta

Interleukin-1beta (IL-1beta) induces anorexia, fever, sleep changes, and neuroendocrine alterations when administered into the brain. Here, we investigated the regulation of the IL-1beta system (ligand, receptors, receptor accessory protein, and receptor antagonist), tumor necrosis factor-alpoha (TNF-alpha), transforming growth factor (TGF)-beta1, and TGF-alpha mRNAs in the hypothalamus of obese (fa/fa) and lean (Fa/Fa) Zucker rats in response to the intracerebroventricular microinfusion of IL-1beta (8.0 ng/24 hr for 72 hr, a dose that yields estimated pathophysiological concentrations in the cerebrospinal fluid). IL-1beta increased IL-1beta, IL-1 receptor types I and II (IL-1RI and IL-1RII), IL-1 receptor accessory protein soluble form (IL-1R AcP II), IL-1 receptor antagonist (IL-1Ra), TNF-alpha, and TGF-beta1 mRNAs in the hypothalamus from obese and lean rats. IL-1beta-induced IL-1beta system and ligand (IL-1beta, TNF-alpha, and TGF-beta1) mRNA profiles were highly intercorrelated in the same samples. Levels of membrane-bound IL-1R AcP and TGF-alpha mRNAs did not change. Heat-inactivated IL-1beta had no effect. The data suggest 1) the operation of an IL-1beta feedback system (IL-1beta/IL-1RI/IL-1R Acp II/IL-1RII/IL-1Ra) and 2) potential cytokine-cytokine interactions with positive (IL-1beta <--> TNF-alpha) and negative (TGF-beta1 --> IL-1beta/TNF-alpha) feedback. Dysregulation of the IL-1beta feedback system and the TGF-beta1/IL-1beta-TNF-alpha balance may have implications for neurological disorders associated with high levels of IL-1beta in the brain.

Topics: Animals; Feedback; Hypothalamus; Interleukin-1; Male; Obesity; Rats; Rats, Zucker; RNA, Messenger; Transforming Growth Factor alpha; Transforming Growth Factor beta

Transforming growth factor-alpha (TGF alpha) and prostaglandin F2 alpha (PGF2 alpha) are potent inhibitors of adipocyte differentiation. We demonstrate here that TGF alpha messenger RNA (mRNA) is expressed in freshly isolated fat pads and in primary culture of adipocyte precursors cultivated in defined medium before and after differentiation. We show that PGF2 alpha stimulated TGF alpha mRNA expression in a dose-dependent manner. PGF2 alpha also stimulated TGF alpha production in the culture medium of adipocyte precursors in primary culture. PGF2 alpha stimulated TGF alpha mRNA expression in both undifferentiated and differentiated cells. 9 alpha,11 beta-PGF2 alpha, which also inhibited adipose differentiation, stimulated TGF alpha mRNA expression similarly to PGF2 alpha, whereas other PGs had no effect on TGF alpha mRNA expression. The time-course experiment indicates that the stimulation of TGF alpha mRNA expression by PGF2 alpha is observed within 6 h of exposure to PGF2 alpha and is inhibited by treatment of the cells with actinomycin D. The effect of PGF2 alpha on TGF alpha expression did not require activation of protein kinase C and was fully reversible. As both TGF alpha and PGF2 alpha are inhibitors of adipose differentiation, it is suggested that stimulation of TGF alpha expression by PGF2 alpha could represent an amplification mechanism to modulate adipocyte precursor differentiation and adipocyte function within the adipose tissue.

Topics: Adipocytes; Adipose Tissue; Animals; Base Sequence; Cell Differentiation; Cells, Cultured; Dinoprost; Growth Substances; Molecular Probes; Molecular Sequence Data; Obesity; Prostaglandins; Protein Kinase C; Rats; Rats, Sprague-Dawley; RNA, Messenger; Stem Cells; Transforming Growth Factor alpha