To Investigate the in Vitro Conversion of 25(Oh)D to 1,25(Oh)D of Breast Cancer Cells and the Expression Changes of Vitamin D-Catalyzing Genes in Normal and Cancerous Breast Tissues

Breast cancer (BCa) is the most common cancer in women in the United States with over 180,000 new cases in 2008 . Estrogens drive the proliferation of mammary epithelial cells and therefore promote the growth of estrogen receptor positive (ER+) BCa. Approximately 70% of BCa is ER+ and is therefore amenable to hormonal treatments that ablate estrogen production or block estrogen action. In spite of the available treatments, the incidence of BCa continues to rise and increasing emphasis is being placed on BCa chemoprevention, including approaches to reduce exposure to carcinogens and the use of nutritional agents to prevent and/or delay the development of BCa. Calcitriol, the hormonally active form of vitamin D (1,25-dihydroxyvitamin D3), plays an important role in calcium homeostasis through its actions in intestine, kidney and bone. In the recent years it has been recognized that in addition to its actions on calcium and bone homeostasis, calcitriol also exhibits anti-proliferative and pro-differentiation activities indicating its potential use in the prevention and treatment of several cancers including BCa. From the epidemiological studies, vitamin D status has been linked with lower incidence of breast cancer and lower mortality of breast cancer victims. Recent studies further demonstrated that vitamin D-related genes, i.e. vitamin D receptor (VDR), CYP24A1( inactivate vitamin D), CYP27B1( activate vitamin D), play crucial roles during breast cancer development. Previously, the final activation step of vitamin D, from 25(OH)D3 to 1,25(OH)2D3 has been deemed taking place in the proximal tubular of kidney through catalyzation by CYP 27B1. It has been shown recently that CYP27B1 indeed presents in a variety of tissues, including breast tissue. This finding leads to the further assumption that breast tissue could convert 25(OH)D3 to 1,25(OH)2D3 by itself and the breast tissue-converted 1,25(OH)2D3 would work in a para- or auto- crine manner. In this proposed study, we aim to demonstrate breast cancer cell is able to convert 25(OH)D3 to 1,25(OH)2D3 in vitro. If we can prove this, we would further test this in vivo by feeding mice with different concentrations of vitamin diets to observe the xenografted breast cancer cells’ growth. In addition, to understand the mechanism by which vitamin D controls the breast cancer cell growth, we would apply the proteomic method and the interested genes found by proteomics would be transfected or downregulated in breast cancer cells to confirm their roles. At the same time , we will collect breast tissues from breast cancer victims to compare the VDR, CYP24A1, and CYP 27 B1 expressions in the normal and cancer tissues to further figure out the role vitamin D plays in the breast cancer. Finally, through our work, we hope we can offer a new strategy for breast cancer prevention and treatment.

Project ID:PC10108-0689
External Project ID:NSC101-2314-B182-052-MY3