Date of Award

1-1-2015

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Biomedical Sciences

Content Description

1 online resource (xiii, 170 pages) : PDF file, color illustrations, color maps

Dissertation/Thesis Chair

JoEllen Welsh

Committee Members

Martin Tenniswood, Tom Begley, Bruce Herron, Melinda Larsen

Keywords

adipose, epithelium, mammary gland, vitamin D, Vitamin D, Mammary glands, Epithelial cells, Breast, Adipose tissues, Cellular signal transduction, Mice

Subject Categories

Cell Biology | Developmental Biology

Abstract

A strong correlation between vitamin D deficiency and increased breast cancer incidence and mortality has been well established, leading researchers to further examine the possibility of using vitamin D in treatment and prevention strategies. Our long term goal is to elucidate the mechanisms by which vitamin D pathway signaling impacts on breast cancer. Generation of the high-affinity vitamin D receptor (VDR) ligand 1,25-dihydroxyvitamin D (1,25-D) from 25-hydroxyvitamin D (25-D) is mediated by CYP27B1 which is present and developmentally regulated in multiple tissues including the mammary gland. We utilized transgenic mouse models combined with diet-induced vitamin D deficiency to determine whether VDR exerts 1,25-D-independent effects on growth, apoptosis or differentiation of mammary epithelial cells. Both in vivo and ex vivo approaches were utilized to establish whether 1,25-D treatment exerts direct effects on mammary gland development. Analysis of the stages of pregnancy allowed observation of the role of vitamin D in the processes of mammary gland remodeling which occurs as a result of complex interactions between the epithelial compartment and adipose-filled stromal compartment. Our data indicate that mammary glands from VDRKO mice display accelerated branching, enhanced sensitivity to estrogen and progesterone and altered gene expression during puberty and early pregnancy, effects which are not recapitulated in glands from CYP27B1KO mice. This suggests that the effects of vitamin D signaling on hormone-mediated epithelial expansion results from VDR activity in the absence of 1,25-D (i.e. either unliganded or bound with an alternate ligand). In contrast, during the apoptotic regression of epithelial cells in involution, parallels can be drawn both in morphology and signaling between glands lacking VDR and 1,25-D, suggesting that apoptosis is impacted by the 1,25-D-VDR complex (i.e. the canonical pathway). Mammary glands in control mice on a high fat “western” diet containing sufficient vitamin D demonstrated increased adiposity and decreased ductal branching which was not observed in mice lacking VDR specifically within the adipose tissue. This suggests a role for the VDR, not only in regulation of epithelial cell growth and apoptosis, but also in stromal adipogenesis. Diet-induced vitamin D deficiency produced a 50% decrease in the circulating levels of 25-D in WT females and a corresponding decrease in the weight of adipose tissues. These changes parallel the adipose tissue atrophy observed in global VDRKO mice but is in contrast to the increase in adipogenesis observed in adipose-specific VDRKO mice. These data suggest that VDR activity is required for adipogenesis in the mammary gland but not via signaling within mature adipocytes. Collectively, these studies have identified novel roles for the VDR and its ligands in mammary gland development that provide insight into the relationship between vitamin D status and breast cancer.

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