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JoEllen Welsh, Ph.D.
Current Research Projects
I. Characterization of mouse models with deregulated vitamin D function.
Like humans with genetic defects in vitamin D function, mice lacking either the vitamin D receptor (VDR) or its ligand 1,25-dihydroxyvitamin D3 exhibit defects in bone and calcium homeostasis. The Welsh lab is studying these mice to determine whether ablation of vitamin D signaling alters cancer risk or progression. To date, our studies have demonstrated an increased risk for skin and mammary cancer in VDR null mice, and current work is focused on determining the underlying molecular mechanisms that promote carcinogenesis in the absence of vitamin D function.
II. Molecular actions of the VDR in triple negative breast cancer.
Recent studies of women with triple negative breast cancer indicate a high prevalence of vitamin D deficiency in this population. The Welsh lab has developed unique cell lines for study of hormone independent breast cancer and has recently characterized the genomic targets of VDR in this model system. Follow up of this data indicates that vitamin D suppresses a cohort of extracellular matrix proteins that facilitate invasion and that predict poor prognosis and reduced disease-free survival in women with breast cancer. We are currently using our model system to define the relevance of these proteins, and their regulation by vitamin D, to invasion and metastasis.
III. Breast cancer prevention by vitamin D.
The VDR is present in normal human breast but its functions in this tissue are poorly understood. We used genomic profiling to characterize the effects of 1,25-dihydroxyvitamin D in normal breast cells and identified over 200 novel VDR gene targets. In particular, we identified a set of vitamin D responsive genes that regulate carbohydrate and amino acid metabolism and we hypothesize that these genes are important for the chemopreventive effect of vitamin D in breast cells. Current efforts are directed at clarifying the interactions between vitamin D, oncogenes and tumor suppressors in control of the cancer-associated metabolic switch (ie, Warburg effect) in relation to breast cancer prevention.
IV. Regulation of innate immunity in mammary epithelial cells by vitamin D.
In normal breast cells, 1,25-dihydroxyvitamin D also markedly enhances the synthesis and secretion of the multi-functional immune protein CD14. In vivo, CD14 is induced during mammary gland remodeling where it may facilitate identification of apoptotic cells. CD14 also activates TLR4 signaling and may promote either anti-inflammatory or pro-inflammatory signaling depending on the specific context. In this project we are using an array of immunological tools to examine how vitamin D induced CD14 regulates the cross-talk between epithelial cells and immune cells in the mammary tissue environment.
V. Effect of vitamin D and the VDR on lineage determination in mesenchymal stem cells.
An interesting phenotype we reported in the VDR null mice is a progressive atrophy of adipose tissue as the animals age. Further experiments demonstrated that the VDR null mice fail to gain weight when placed on a high fat diet which readily induces obesity in normal animals. In this project we are using human adipose derived stem cells to identify the molecular mechanisms whereby vitamin D alters adipogenesis. Initial results suggest that vitamin D may alter insulin sensitivity through regulation of the metalloreductase protein STEAP4.