Post-Doctoral Fellow Kara DeSantis was awarded a Ruth L. Kirschstein Postdoctoral Individual National Research Service Award (F32) to study the role of VDR in salivary gland homeostasis and cancer. While rare, salivary cancer is often lethal and is typically resistant to standard cancer treatments. We have demonstrated that VDR is expressed in normal salivary gland and is retained in early stages of salivary cancer. Our project is studying the interactions of vitamin D with vitamin A (retinoid) signaling in the regulation of cell lineage determination in normal and cancerous salivary tissue.
Funded since 1995 by the NIH, the Welsh lab has extensively characterized the impact of vitamin D and the vitamin D receptor (VDR) on breast cancer development and progression. The group was the first to demonstrate that 1,25-dihdroxycholecalciferol (1,25D) activated apoptosis or cell death in cancer cells - both in culture models and xenografted human tumors. They also characterized the impact of the VDR on normal breast development during puberty, pregnancy and lactations and determined how ablation of the VDR altered the course of breast cancer in animal models. More recently, the Welsh lab has utilized state of the art genomic approaches to catalog genomic profiles in cells and tumors exposed to VDR ligands.
Our current project focuses on the control of hyaluronan synthesis by the vitamin D pathway. Hyaluronic acid (HA) is an extracellular polymer synthesized by membrane-bound hyaluron synthases (coded by three HAS genes). We found that HAS2 is strongly down-regulated by 1,25D in breast cancer cells, which disrupts HA synthesis and signaling. HA signaling has been linked to survival of breast cancer stem cells via its ability to stimulate CD44, therefore down regulation of the HA pathway is predicted to eliminate the stem cell population. We are studying the regulation of stem cell survival by 1,25D and other natural products in models of triple negative breast cancer.
This project is funded by NIH CA1945001 to J. Welsh, read more HERE
MORE INFO - our publications on Vitamin D and Breast Cancer
This new project, funded by the Department of Defense Breast Cancer Research Program, is investigating the role of gamma-carboxylation, a rare post-translational modification, on breast cancer biology. Gamma carboxylation is catalyzed by a group of enzymes (GGCX, VKORC1, VKORC1L1) which are expressed in normal breast and in a subset of breast cancers. Women whose tumors express high levels of GGCX, VKORC1 and/or VKORC1L1 experience a more aggressive disease course, suggesting that blocking this pathway may offer therapeutic benefit. GGCX activity is dependent on vitamin K, a fat soluble vitamin which has not been well studied in breast cancer. Our preliminary studies indicate that vitamin K exposure alters the pattern of gamma carboxylated proteins synthesized by breast cancer cells, and we are actively working to identify these vitamin K regulated proteins in order to study their effects on tumor progression.
This project is funded by a FY2016 BCRP Breakthrough Level 1 grant (BC151516) to J Welsh.
DOWNLOAD our poster presentation from the San Antonio Breast Cancer Symposium (December 2016)
DOWNLOAD 2019 Publication in Oncotarget