Breast Cancer and Estrogen Biosynthesis in Adipose Tissue

The long-term objective of this application was to determine the cellular and molecular mechanisms responsible for increased aromatase expression in breast adipose fibroblasts proximal to malignant epithelial cells. Our results are supportive of the following hypothesis Regional differences in relative proportions of histological components of the breast adipose tissue e.g., fibroblasts vs. mature adipocytes may be the primary cause of estrogenic concentration gradients, since regions containing higher numbers of fibroblasts are the sites of increased aromatase expression and increased rate of tumor development. Although the initiating events are unknown, malignant cells in the regions displaying higher aromatase expression are more likely to proliferate. Secretory products of the tumor stimulated by estrogen may in turn further increase aromatase expression in the surrounding adipose tissue. These products will additionally stimulate proliferation of aromatase-expressing fibroblasts to generate a fibrous capsule around the tumor, i.e., desmoplastic reaction. Estrogens will continue to positively influence neoplastic growth by increasing the expression of secretory products and their receptors in the tumor tissue. Thus, a positive feed-back loop is established in which locally-produced estrogen and tumor-derived factors e.g., cytokines, growth factors and prostaglandins act by paracrine and autocrine mechanisms to sustain the growth and development of the tumor.