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Vitamin K: Body Pools and Function in Breast Cancer

维生素 K：乳腺癌中的身体储备和功能

基本信息

批准号：
10524195
负责人：
JoEllen Welsh
金额：
$ 11.17万
依托单位：
STATE UNIVERSITY OF NEW YORK AT ALBANY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-09 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10524195
关键词：
Adverse effects Affect Breast Cancer Cell Breast Cancer cell line Cancer Biology Cell Respiration Cell model Cells Coagulation Process Data Data Set Diet Dimethylallyltranstransferase Disease Energy Metabolism Enzymes Gene Expression Generations Genes Growth Histology Homeostasis In Vitro Intake Link Mammary Neoplasms Mammary gland Mammospheres Masks Measures Mediating Metabolism Mus Oncogenes Oxidoreductase Pathway interactions Patients Phenotype Physiological Protein Biosynthesis Proteins Proteomics Role Testing The Cancer Genome Atlas Therapeutic Tissues Translations Tumor Biology Tumor Subtype Vitamin K Vitamin K 1 Vitamin K 2 Woman Xenograft procedure advanced breast cancer aggressive breast cancer aldehyde dehydrogenase 1 bone cancer genomics carboxylate carboxylation cell growth clinically relevant cofactor dietary enzyme biosynthesis feeding gamma-glutamyl carboxylase ginsenoside M1 in vivo insight loss of function malignant breast neoplasm migration patient subsets protein function response restoration screening stem cell biomarkers stem cells therapeutic target triple-negative invasive breast carcinoma tumor tumor growth tumor progression uptake

项目摘要

PROJECT SUMMARY/ABSTRACT This proposal focuses on the divergent effects of the two major dietary forms of vitamin K on breast cancer. K vitamins act as cofactors for gamma-glutamyl carboxylase (GGCX), which post-translationally introduces γ- carboxyglutamate residues into proteins. Although most of the 17 known γ-carboxylated proteins function in coagulation and bone homeostasis, the presence of GGCX in most tissues (including mammary gland) suggests more extensive physiological roles for vitamin K. We have demonstrated that triple negative breast cancer (TNBC) cell lines express GGCX and produce γ-carboxylated proteins in response to vitamin K1 (phylloquinone), the major dietary form. In TNBC cells, K1 treatment enriches for the stem cell marker aldehyde dehydrogenase 1 (ALDH1) and promotes mammosphere formation. These data suggest that K1 sustains GGXC mediated γ- carboxylation to drive aggressive breast cancer phenotypes. Through analysis of genomic cancer datasets, we find that ~25% of breast tumors express GGCX and the vitamin K oxidoreductase (VKOR) genes required for its activity. Patients with such tumors have poorer survival than those whose tumors do not express these genes at high levels. Patients with this subtype of tumor would be candidates for therapies that limit K1 availability and/or inhibit GGCX. Surprisingly, we found that vitamin K2 (menaquinone-4), another naturally occurring form present in diet, does not stimulate γ-carboxylation or stem cell phenotypes in TNBC cells, but instead strongly suppresses cell growth, migration and energy metabolism. These provocative data indicate that K1 and K2 exert distinct effects on breast cancer cells, with K1 promoting and K2 suppressing aggressive phenotypes. We also found that expression of the vitamin K2 biosynthesis enzyme UbiA Prenyltransferase Domain Containing 1 (UBIAD1) is undetectable in TNBC, suggesting altered cellular handling of vitamin K. In Aim 1 we will dissect the effects of K1 and K2 in vitro, evaluate the role of UBIAD1 and conduct feeding studies to measure accumulation of K1 and K2 in TNBC xenografts and host mammary gland in relation to tumor growth. In Aim 2 we will determine whether deletion of GGCX from TNBC cells impacts γ-carboxylated protein synthesis and aggressive phenotypes in vitro and in vivo. Aim 3 will identify relevant γ-carboxylated GGCX substrate proteins that mediate the effects of K1. We anticipate that growth of tumors with high GGCX activity and low UBIAD1 will be stimulated by high dietary K1 and inhibited by high dietary K2. These findings would identify GGCX as an oncogene and the vitamin K pathway as a therapeutic target in a subset of patients with advanced breast cancer.

项目总结/文摘