Dataset Information

Pubertal high fat diet: effects on mammary cancer development.

ABSTRACT:

Introduction

Epidemiological studies linking dietary fat intake and obesity to breast cancer risk have produced inconsistent results. This may be due to the difficulty of dissociating fat intake from obesity, and/or the lack of defined periods of exposure in these studies. The pubertal mammary gland is highly sensitive to cancer-causing agents. We assessed how high fat diet (HFD) affects inflammation, proliferative, and developmental events in the pubertal gland, since dysregulation of these can promote mammary tumorigenesis. To test the effect of HFD initiated during puberty on tumorigenesis, we utilized BALB/c mice, for which HFD neither induces obesity nor metabolic syndrome, allowing dissociation of HFD effects from other conditions associated with HFD.

Methods

Pubertal BALB/c mice were fed a low fat diet (12% kcal fat) or a HFD (60% kcal fat), and subjected to carcinogen 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumorigenesis.

Results

HFD elevated mammary gland expression of inflammatory and growth factor genes at 3 and 4 weeks of diet. Receptor activator of nuclear factor kappa-B ligand (RANKL), robustly induced at 4 weeks, has direct mitogenic activity in mammary epithelial cells and, as a potent inducer of NF-?B activity, may induce inflammatory genes. Three weeks of HFD induced a transient influx of eosinophils into the mammary gland, consistent with elevated inflammatory factors. At 10 weeks, prior to the appearance of palpable tumors, there were increased numbers of abnormal mammary epithelial lesions, enhanced cellular proliferation, increased growth factors, chemokines associated with immune-suppressive regulatory T cells, increased vascularization, and elevated M2 macrophages. HFD dramatically reduced tumor latency. Early developing tumors were more proliferative and were associated with increased levels of tumor-related growth factors, including increased plasma levels of HGF in tumor-bearing animals. Early HFD tumors also had increased vascularization, and more intra-tumor and stromal M2 macrophages.

Conclusions

Taken together in this non-obesogenic context, HFD promotion of inflammatory processes, as well as local and systemically increased growth factor expression, are likely responsible for the enhanced tumorigenesis. It is noteworthy that although DMBA mutagenesis is virtually random in its targeting of genes in tumorigenesis, the short latency tumors arising in animals on HFD showed a unique gene expression profile, highlighting the potent overarching influence of HFD.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC3978633 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Pubertal high fat diet: effects on mammary cancer development.

Zhao Yong Y Tan Ying Siow YS Aupperlee Mark D MD Langohr Ingeborg M IM Kirk Erin L EL Troester Melissa A MA Schwartz Richard C RC Haslam Sandra Z SZ

Breast cancer research : BCR 20130101 5

<h4>Introduction</h4>Epidemiological studies linking dietary fat intake and obesity to breast cancer risk have produced inconsistent results. This may be due to the difficulty of dissociating fat intake from obesity, and/or the lack of defined periods of exposure in these studies. The pubertal mammary gland is highly sensitive to cancer-causing agents. We assessed how high fat diet (HFD) affects inflammation, proliferative, and developmental events in the pubertal gland, since dysregulation of t ...[more]

PMID: 24156623

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Project description:BackgroundEpidemiological studies have shown that consumption of a high-fat diet (HFD) increases the risk of developing breast cancer (BC). Studies in rodents have shown HFD causes changes in the genetic programming of the maturing mammary gland (MG) increasing the susceptibility of developing the disease. Less is known about how HFD induced genes impact BC development. HFD exposure two weeks before conception to six weeks of age was previously shown to dramatically change MG gene expression in 10 week old mice. Therefore, we investigated these differentially expressed HFD-induced genes for their expression in BC using the NKI 295 breast tumor dataset.ResultsTo examine the potential role of HFD induced genes in BC, we first investigated whether these HFD-induced genes in mouse MGs were differentially expressed in different types of human BC. Of the 28 HFD induced genes that were differentially expressed between BC subtypes in the NKI set, 79% were significantly higher in basal-like BC. Next, we analyzed whether HFD induced genes were associated with BC prognosis utilizing gene expression and survival data for each HFD induced gene from the NKI data and constructed Kaplan Meier survival plots. Significantly, 93% of the prognosis associated genes (13/14) were associated with poor prognosis (P = 0.002). Kaplan Meier analysis with 249 non-basal-like BC found that all but one of the genes examined were still significantly associated with poor prognosis. Furthermore, gene set enrichment analysis (GSEA) with HFD microarray data revealed that invasive BC genes where enriched in HFD samples that also had lost expression of luminal genes.ConclusionsHFD exposed mouse MGs maintain differential expression of genes that are found highly expressed in basal-like breast cancer. These HFD-induced genes associate with poor survival in numerous BC subtypes, making them more likely to directly impact prognosis. Furthermore, HFD exposure leads to a loss in the expression of luminal genes and a gain in expression of mesenchymal and BC invasion genes in MGs. Collectively, our study suggests that HFD exposure during development induces genes associated with poor prognosis, thus identifying how HFD diet may regulate BC development.

Project description:Background: Post-menopausal obesity is an established risk factor for breast cancer. Consumption of diets high in fat is known to be highly correlated with obesity. In this, we sought to evaluate the interaction(s) between high fat diet, weight gain and mammary carcinogenesis using an obese-resistant and obese-prone rat model with direct correlates to human disease. Methods: Female obese-prone (OP) and obese-resistant (OR) weanling rats were placed on either a low fat (10% kcal) or a high fat (39% kcal) n-6 polyunsaturated (PUFA) safflower diet for 30 days. At post natal day (PND) 50, global gene expression profiling was performed on microdissected mammary epithlelium from one cohort of rats and another cohort of rats were given a single oral gavage of either 7,12-dimethylbenz[a]anthracene (DMBA at 14 mg/kg) or vehicle. Rats were then maintained on the diets and body weights, food consumption and development of mammary lesions were monitored weekly. Results: The DMBA-treated OR rats on the 39% safflower diet had significantly greater incidence of ductal carcinoma-in-situ (DCIS) lesions and significantly greater DCIS multiplicity than DMBA-treated OR rats on the 10% safflower diet. These differences were not seen in the OP strain. Gene expression analysis of mammary ductal epithelium from OR rats on the high fat diet showed significant upregulation of proliferation-related genes compared to those consuming the low fat safflower diet. Again, these differences were not seen in the OP strain. Conclusion: Our findings indicate that consumption of high fat safflower diet enhances mammary carcinogenesis in an OR rat strain through increased proliferation of mammary epithelium at the time of exposure, but not in the OP rat strain. Thus, the diet-induced increase in sensitivity was strain-specific and independent of weight gain or obesity level. Female obese-prone (OP) and obese-resistant (OR) weanling rats were placed on either a low fat (10% kcal) or a high fat (39% kcal) n-6 polyunsaturated (PUFA) safflower diet for 30 days. At post natal day (PND) 50, global gene expression profiling was performed on microdissected mammary epithlelium from one cohort of rats and another cohort of rats were given a single oral gavage of either 7,12-dimethylbenz[a]anthracene (DMBA at 14 mg/kg) or vehicle. Rats were then maintained on the diets and body weights, food consumption and development of mammary lesions were monitored weekly.

Dataset Information

Pubertal high fat diet: effects on mammary cancer development.

Introduction

Methods

Results

Conclusions

Publications

Pubertal high fat diet: effects on mammary cancer development.

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