1,25(OH)2 vitamin D3 (1,25D) and the vitamin D3 receptor (VDR) regulate cell cycle, differentiation, and apoptosis in the normal mammary gland and in breast cancer cells. The enzyme that catalyzes the production of 1,25(OH)2D3 is the 25-hydroxyvitamin D [25(OH)D3] 1alpha-hydroxylase (1-OHase). Although initially thought to be exclusively expressed in kidney, we have demonstrated expression of 1-OHase in human mammary epithelial cells and in normal murine mammary gland. These studies will test the hypothesis that normal breast tissue expresses 1-OHase and generates 1,25(OH)2D3 which activates VDR locally to inhibit growth and maintain differentiation of mammary epithelial cells. This hypothesis suggests that vitamin D metabolizing enzymes and the VDR play key roles in nutritional regulation of gene expression in mammary gland. A corollary to this hypothesis is that deregulation of 1,25(OH)2D3 production or action at the tissue level may be associated with neoplastic progression of the breast. The following specific aims will test this hypothesis and its implications:
Aim 1. To demonstrate a functional role for the 25(OH) vitamin D 1-OHase in mammary gland;
Aim 2. To examine metabolism, uptake and transport of vitamin D steroids in mammary epithelial cells;
Aim 3. To determine whether non-genomic signaling contributes to the effects of VDR on breast cancer cell growth. Our approaches will include both in vitro and in vivo model systems including both normal and transformed cell lines derived from mice with targeted deletion of 1-OHase or VDR. These studies will provide mechanistic detail on the functions of the vitamin D signaling pathway in mammary gland in relation to prevention and treatment of breast cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ogunbiyi, Peter
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Notre Dame
Schools of Arts and Sciences
Notre Dame
United States
Zip Code
Welsh, JoEllen (2018) Vitamin D and breast cancer: Past and present. J Steroid Biochem Mol Biol 177:15-20
Welsh, JoEllen (2017) Function of the vitamin D endocrine system in mammary gland and breast cancer. Mol Cell Endocrinol 453:88-95
Matthews, Donald G; D'Angelo, Joseph; Drelich, Jordan et al. (2016) Adipose-specific Vdr deletion alters body fat and enhances mammary epithelial density. J Steroid Biochem Mol Biol 164:299-308
Beaudin, Sarah G; Robilotto, Samantha; Welsh, JoEllen (2015) Comparative regulation of gene expression by 1,25-dihydroxyvitamin D3 in cells derived from normal mammary tissue and breast cancer. J Steroid Biochem Mol Biol 148:96-102
Rhieu, Steve Y; Annalora, Andrew J; LaPorta, Erika et al. (2014) Potent antiproliferative effects of 25-hydroxy-16-ene-23-yne-vitamin D? that resists the catalytic activity of both CYP27B1 and CYP24A1. J Cell Biochem 115:1392-402
LaPorta, Erika; Welsh, JoEllen (2014) Modeling vitamin D actions in triple negative/basal-like breast cancer. J Steroid Biochem Mol Biol 144 Pt A:65-73
Keith, Meggan E; LaPorta, Erika; Welsh, JoEllen (2014) Stable expression of human VDR in murine VDR-null cells recapitulates vitamin D mediated anti-cancer signaling. Mol Carcinog 53:286-99
Narvaez, C J; Simmons, K M; Brunton, J et al. (2013) Induction of STEAP4 correlates with 1,25-dihydroxyvitamin D3 stimulation of adipogenesis in mesenchymal progenitor cells derived from human adipose tissue. J Cell Physiol 228:2024-36
Welsh, JoEllen (2012) Cellular and molecular effects of vitamin D on carcinogenesis. Arch Biochem Biophys 523:107-14
Welsh, JoEllen; Zinser, Lindsay N; Mianecki-Morton, Laurel et al. (2011) Age-related changes in the epithelial and stromal compartments of the mammary gland in normocalcemic mice lacking the vitamin D3 receptor. PLoS One 6:e16479

Showing the most recent 10 out of 42 publications