# Interrupting tumor progression by restoration of VDR expression

> **NIH NIH R21** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2023 · $225,410

## Abstract

Project Summary
Vitamin D has shown cancer preventive benefit in colorectal cancer (CRC). Despite some positive findings,
conflicting data is also evident in human intervention trials that further study is warranted. An important
observation linking the limited effects of vitamin D is a significant reduction in the levels of vitamin D receptor
(VDR) activity. Our recent study in ApcΔ14/+ mice showed a loss of VDR expression in intestinal polyps, most
likely accounting for the lack of cancer protection afforded by high-dose vitamin D3. Further analysis in this study
and results of others suggested that compromised VDR expression may have influence on the regulation of β-
catenin activation. Based on these observations, we hypothesize that forced re-expression of VDR within
intestinal tumors can restore β-catenin control and potentially promote tumor regression in ApcΔ14/+ mice. To test
this hypothesis, we will use our recently developed mouse model, Scd3iCreER/+, in which the expression of a floxed
transgene can be driven specifically to intestinal tumors. To control VDR expression, we will utilize a floxed-
stop system, in which Vdr expression is restricted by a STOP sequence until tamoxifen-controlled Cre
recombinase is expressed. The successful creation of this conditional mouse model will allow us to directly test
the influence of timed VDR expression on tumor regression in the intestine. In Aim 1, we plan to generate
ROSA26LSL-Vdr-GFP mice, and then a compound mutant mice, ApcΔ14/+:ROSA26LSL-Vdr-GFP:Scd3iCreER/+. These
mouse models will be thoroughly characterized to confirm the forced expression of VDR within intestinal tumors.
In Aim 2, using the ApcΔ14/+:ROSA26LSL-Vdr-GFP:Scd3iCreER/+ mice, we will examine the impact of exogenous VDR
reactivation on intestinal tumor development in a spatio-temporal manner. We will also profile the gene
expression changes associated with the re-expression of VDR, focusing on the interplay between VDR and
Wnt/β-catenin signaling pathways. Aim 3 will investigate the effect of exogenous expression of VDR on immune
cell trafficking within the tumor microenvironment using cyTOF analysis. These proposed exploratory studies will
provide a clear understanding of the anticancer activities of VDR, and ultimately enable us to uncover new
therapeutic strategies for the reactivation of repressed VDR in CRC.

## Key facts

- **NIH application ID:** 10591578
- **Project number:** 5R21CA270973-02
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Masako Nakanishi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $225,410
- **Award type:** 5
- **Project period:** 2022-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10591578

## Citation

> US National Institutes of Health, RePORTER application 10591578, Interrupting tumor progression by restoration of VDR expression (5R21CA270973-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10591578. Licensed CC0.

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