The role of adiponectin in mammary gland development
Abstract
Adiponectin is an insulin-sensitizing hormone that is secreted from adipocytes. Clinical studies have linked low adiponectin levels to increased risk of atherosclerosis, type II diabetes, metabolic syndrome and many forms of cancer. Subsequent studies have shown adiponectin has anti-atherogenic, anti-diabetic and anti-inflammatory effects. Recent evidence also reveals adiponectin inhibits proliferation of breast cancer and nonmalignant mammary epithelial cell lines in vitro . As mammary development studies have helped define actions of hormones on epithelial behavior it has also become evident that many hormones critical for development are also important players in breast cancer. To date, there has been no examination of the role of adiponectin in non-malignant mammary epithelia in vivo. The objective of this study was to gain insight into the potential role of adiponectin in normal mammary gland development. Towards this objective, our studies determined the expression profiles of mammary adiponectin and its receptors (AR1 and AR2) through the four main stages of development: virgin, pregnancy, lactation and involution. In brief, we found mammary adiponectin and AR1/AR2 (mRNA and protein) levels significantly decreased during lactation while increasing again at involution. Also observed was dramatic shift in mammary-associated adiponectin isoforms during distinct developmental stages. Together, this data suggests a reduction in adiponectin signaling, and modulation of adiponectin isoforms, may be necessary for mammary epithelial proliferation to ensue during pregnancy. Furthermore, increased adiponectin action at involution may be important for promoting epithelial apoptosis after lactation. The increased adiponectin observed at involution merited further investigation into the effect of this hormone on differentiated mammary epithelia. During development the process of involution is characterized by massive epithelial apoptosis as marked mammary gland remodeling occurs. The effect of adiponectin on the lactating mammary gland was examined by measuring key markers of mammary cell apoptosis (STAT3 and Bax) in a mammary explant culture model. In brief, adiponectin, in the absence of lactogenic hormones, increased activation of STAT3 and Bax expression. The presence of lactogenic hormones prevented adiponectin activation of epithelial apoptosis. We also provide evidence that adiponectin does not effect lactation mechanisms as β-casein expression, a marker for milk production, did not significantly differ between treated groups. Ultimately, these described findings provide a basis for further study of adiponectin mechanisms during mammary involution process, and suggest the regulation of adiponectin action may be a critical towards mammary epithelial apoptosis in vivo. A better understanding of the significance of adiponectin in development will provide novel insights into the role of adiponectin in mammary epithelial biology and breast cancer.
Degree
Ph.D.
Advisors
Camarillo, Purdue University.
Subject Area
Physiology
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