MicroRNA-140 Regulation of the Mammary Microenvironment

Abstract

The heterogeneous cell population found within the mammary microenvironment is essential for both normal mammary gland health and disease development. Despite the importance of the mammary microenvironment, surprisingly little is known concerning the processes regulating mammary microenvironment homeostasis, and how dysregulation of stromal cell signaling pathways promotes mammary gland pathologies, including obesity, fibrosis, and breast cancer. There are over 40 million obese women in the U.S., and 60,000 new cases of obesity-related breast cancer diagnosed every year. Therefore, it is crucial that researchers fully characterize the mechanisms governing obesity, as well as the relationship between obesity and breast cancer initiation and progression. miR-140 was first identified as a regulator of chondrocyte differentiation, and we have shown that miR-140 is a tumor suppressor miRNA that inhibits cancer stem cell signaling in breast cancer. However, the roles of miR-140 in the stromal cells surrounding the mammary gland remain undefined. We recently found that miR-140 was highly expressed in preadipocyte cells, leading us to predict that miR-140 may play a role in adipocyte differentiation and the mammary microenvironment. Based on these preliminary data, we hypothesized that miR-140 is a primary regulator of mammary microenvironmental homeostasis, and that dysregulation of miR-140 in mammary gland stromal cells may promote breast cancer development and progression. Through the experiments detailed in this dissertation, we came to three distinct conclusions: 1. That miR-140 is an essential regulator of adipogenesis, 2. That mammary gland stromal cell expression of miR-140 is downregulated by a high-fat diet, and 3. That loss of miR-140 expression promotes the differentiation of the pathologic myofibroblast cell type. These data demonstrate that miR-140 is a key regulator of stromal cell homeostasis in the mammary microenvironment and implicate re-expression of miR-140 in the obese microenvironment as a potential therapeutic strategy for both the prevention and treatment of breast cancer.