The contributions of adipocytes to mammary gland development and tumor growth

Abstract

Adipocytes represent one of the most abundant constituents of the stromal compartment of the mammary gland. Although we have learned to appreciate the pivotal role stromal cells play in mammary gland development and tumorigenesis growing evidence underscores the need for a better understanding of adipocyte interaction in both normal and tumorigenic mammary gland physiology.;Our approach focuses on a selective and inducible depletion of adipocytes. Using our previous developed FAT-ATTAC mouse model, I have demonstrated that adipocytes regulate ductal elongation, lateral branching and terminal end bud formation during puberty, and are required for the maintenance of the normal architecture in the adult tissue, thus demonstrating the direct physiological impact of adipocytes on mammary gland morphogenesis.;This interaction becomes particularly relevant in the context of mammary tumorigenesis. Here, I focus on the contributions of one of the more important adipokines, adiponectin. Serum concentrations of adiponectin negatively correlate with body mass index, insulin resistance and breast cancer risk. To explore the association of adiponectin with breast cancer, I used the mouse MMTV-PyMT mammary tumor model. I compared the rates of tumor growth in MMTV-PyMT mice in a wildtype and adiponectin null background. Histology and MicroPET imaging show that the rate of tumor growth is significantly reduced in the absence of adiponectin at early stages. PyMT/adiponectin knockout mice exhibit a reduction in their angiogenic profile resulting in nutrient deprivation of the tumors and tumor-associated cell death. Surprisingly, in more advanced malignant stages of the disease mice lacking adiponectin give rise to a larger tumor burden, an increase in the mobilization of circulating endothelial progenitor cells and a gene expression fingerprint indicative of more aggressive tumor cells.;These observations indicate that adiponectin has potent angio-mimetic properties in tumor vascularization. However, in tumors deprived of adiponectin, this anti-angiogenic stress results in an adaptive response that fuels tumor growth via mobilization of circulating endothelial progenitor cells and the development of mechanisms enabling massive cell growth despite a chronically hypoxic microenvironment. Our data may suggest a possible mechanism for the increased risk seen in breast cancer patients with low serum APN such as in obese women.