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Carcinogenesis Advance Access published online on August 27, 2004
Carcinogenesis, doi:10.1093/carcin/bgh271
© 2004 by Oxford University Press
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Received June 11, 2004
Revised July 28, 2004
Accepted August 10, 2004

CANCER BIOLOGY

Vitamin D receptor status alters mammary gland morphology and tumorigenesis in MMTV-neu mice

Glendon M. Zinser 1 JoEllen Welsh 1*

1 Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556


  Abstract

The vitamin D3 receptor (VDR) is a ligand dependent transcription factor implicated in regulation of cell cycle, differentiation and apoptosis of both normal and transformed cells derived from mammary gland. In these studies, we examined whether VDR status altered mammary gland morphology or transformation in the well characterized MMTV-neu transgenic model of breast cancer. We demonstrate that VDR protein is highly expressed in neu-positive epithelial cells of pre-neoplastic lesions, established tumors and lung metastases from MMTV-neu mice. Furthermore, MMTV-neu mice lacking VDR exhibit abnormal mammary ductal morphology characterized by dilated, distended ducts containing dysplastic epithelial cells. From 12 months of age on, MMTV-neu mice lacking VDR also experience body weight loss, atrophy of the mammary fat pad, estrogen deficiency and reduced survival. The limited survival of MMTV-neu mice lacking VDR precluded an accurate assessment of the impact of complete VDR ablation on tumor development. MMTV-neu mice heterozygous for the VDR, however, did not exhibit body weight loss, mammary gland atrophy or compromised survival. Compared to MMTV-neu mice with two copies of the VDR gene, haploinsufficiency of VDR shortened the latency and increased the incidence of mammary tumor formation. Tumor histology and expression/subcellular localization of the neu transgene were not altered by VDR haploinsufficiency despite a significant decrease in tumor VDR expression. Collectively, these studies suggest that VDR gene dosage impacts on age related changes in ductal morphology and oncogene induced tumorigenesis of the mammary gland in vivo.

Keywords: Vitamin D receptor; mammary; MMTV-Neu; breast cancer.
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