Epidemiological studies provide strong evidence that obesity and the associated adipose tissue inflammation are risk factors for breast cancer; however, the molecular mechanisms are poorly understood. We evaluated the effect of a high-fat/high-calorie diet on mammary carcinogenesis in the immunocompetent MMTV-PyMT murine model. Four-week old female mice (20/group) were randomized to receive either a high-fat (HF; 60% kcal as fat) or a low-fat (LF; 16% kcal) diet for eight weeks. Body weights were determined, and tumor volumes measured by ultrasound, each week. At necropsy, the tumors and abdominal visceral fat were weighed and plasma collected. The primary mammary tumors, adjacent mammary fat, and lungs were preserved for histological and immunohistochemical examination and quantification of infiltrating macrophages, crown-like structure (CLS) formation, and microvessel density. The body weight gains, visceral fat weights, the primary mammary tumor growth rates and terminal weights, were all significantly greater in the HF-fed mice. Adipose tissue inflammation in the HF group was indicated by hepatic steatosis, pronounced macrophage infiltration and CLS formation, and elevations in plasma monocyte chemoattractant protein-1 (MCP-1), leptin and proinflammatory cytokine concentrations. HF intake was also associated with higher tumor-associated microvascular density and the proangiogenic factor MCP-1. This study provides preclinical evidence in a spontaneous model of breast cancer that mammary adipose tissue inflammation induced by diet, enhances the recruitment of macrophages and increases tumor vascular density suggesting a role for obesity in creating a microenvironment favorable for angiogenesis in the progression of breast cancer.
Adipose tissue contributes to obesity-associated risk in breast cancer progression. Recent work has demonstrated the involvement of preadipocytes in promoting the induction of breast tumor cell migration and invasion. Neuropeptide Y (NPY) stimulates proliferation of preadipocytes in vitro by the Y1 receptor. NPY receptors are present in almost all primary breast cancers and in lymph node metastases from ER-positive primary cancers. By contrast, the peptide has been shown to inhibit the invasion of certain tumor cells. However, the relative contribution of adipose and NPY to breast tumor survival remains to be determined. Using the highly metastatic ER-negative human breast cancer cell line MDA-MB-231, we found that NPY significantly inhibited cell proliferation, an effect that was reversed by treatment with the Y1-receptor antagonist BIBP-3226 (P<0.05). Breast tumor cells treated with NPY exhibited changes in cell morphology and demonstrated a two-fold increase in early apoptosis. When breast tumor cells were incubated in the presence of conditioned media harvested from 3T3-L1 preadipocytes, NPY enhanced apoptosis. Significantly more breast tumor cells migrated toward the preadipocytes compared to conditioned media alone (P<0.0001), but less in the presence of NPY. In conclusion, it appears that adipose tissue promotes breast tumor survival and migration, while NPY limits its. It will be of interest to determine whether the tumor migration-promoting activity of preadipocytes varies among breast cancer subtypes, and if so, whether it serves as a predisposing factor for breast cancer progression. In addition, the targeting of NPY-Y1 receptors in breast tumors may have a diagnostic and possibly therapeutic value. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1213. doi:10.1158/1538-7445.AM2011-1213
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.