The broad scope of my research program is to understand the hormonal regulation of mammary gland physiology as it relates to normal growth, development and lactation, and how dysregulation of endocrine systems contributes to breast cancer. My projects utilize both in vitro cell systems as well as whole animal rodent models and have applications for both animal agriculture and human health. At present, my research is focused in two areas.
Physiological Roles of IGF and IGFBP in the mammary gland and breast cancer
A long-standing interest of the lab examines insulin-like growth factor (IGF) physiology. The IGFs are peptide growth factors that regulate cell proliferation, differentiation, survival, and migration. These processes are critical to both normal mammary gland development and lactation as well as tumorigenesis and metastasis. The IGFs associate with a family of high affinity binding proteins (IGFBPs) that function to transport the IGFs in the circulation and prolong their half-life. In addition, IGFBPs act at the cellular level to either enhance or inhibit the biological actions of IGFs as well as many other agents that affect cell growth, survival and migration. Many of these effects are independent of binding to IGF, although the precise mechanisms are generally unknown. We have used small interfering RNA and CRISPR gene editing technology to identify an IGF-independent role for IGFBP-3 in the intrinsic apoptotic stress pathway in mammary epithelial cells. This cell type is responsible for milk synthesis and is also a common site of origin of mammary carcinoma. Present studies aim to identify the specific mechanisms by which IGFBP-3 contributes to apoptosis in mammary epithelial cells. Additional areas of interest include the role of IGFBP-5 in regulating growth, differentiation and apoptosis of stromal fibroblasts and interactions between the stromal and epithelial compartments in the mammary gland that regulate these processes.
Alcohol Exposure and Breast Cancer Risk
The Developmental Origins of Heath and Disease (DoHAD) hypothesis proposes that a suboptimal fetal environment can affect lifelong susceptibility to diseases such as obesity, diabetes, heart disease and cancer. Since alcohol intake is a risk factor for breast cancer, we proposed that alcohol exposure during pregnancy may preprogram the mammary gland for an increased risk of mammary tumor development in adulthood. This is an important public health issue as a significant number of women continue to drink during pregnancy and recent studies indicate that the prevalence of fetal alcohol spectrum disorders may be underestimated. Thus, women whose mothers consumed alcohol when they were pregnant may represent a previously unrecognized group of women at risk for developing breast cancer. Our studies have shown that adult rats exposed to alcohol in utero exhibit more mammary tumors in response to a carcinogen and that these tumors exhibit a phenotype predictive of a poorer outcome and that mammary tissue of prepubertal rats exposed to alcohol in utero is hyper-proliferative. The IGF and estrogen signaling systems cross-talk at multiple levels and both factors are positive promoters of tumorigenesis. Furthermore, alcohol increases circulating estrogen levels and is proposed to contribute to its ability to increase breast cancer risk. We have found several parameters of the IGF and estrogen systems to be altered in animals exposed to alcohol in utero. Our current projects are aimed at identifying specific mechanisms by which alcohol exposure in utero or during adulthood may increase risk of mammary tumorigenesis. We are currently testing the hypothesis that alcohol exposure, either during fetal development or in adulthood, may target the mammary epithelial cell hierarchy, shifting it towards one that favors tumorigenesis. These studies are being performed in transgenic mice that express the wnt-oncogene, which promotes mammary tumors in mice.