Vitamin D's role in normal and neoplastic breast development
Hasan, Nafis.
2019
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Vitamin D deficiency has been linked with increased risk of breast
cancer in human populations across latitudes and ethnicities, and with worse
outcomes in breast cancer patients. However, randomized clinical trials have yet
to provide conclusive evidence on the efficacy of vitamin D3 as a therapeutic or
preventive option for breast cancer. Considering that cancer is development gone
awry, it ... read moreis necessary to study vitamin D3's role in breast development. Vitamin D
receptor KO mice show a florid phenotype in the mammary gland during key
developmental stages, i.e., increased ductal extension, branching and number of
terminal end buds during puberty, precocious alveologenesis during pregnancy and
delayed postlactational involution. These morphological changes are largely
influenced by the hormones estrogen, progesterone and prolactin; however, little
is known about vitamin D3's interactions with these hormones at the tissue level
of biological organization. Here, we use multiple 3D culture models that
recapitulate above-mentioned morphological changes in the mammary gland epithelium
in vitro to study vitamin D3's effects, both autonomous and in the context of
estrogen, on organization of the mammary epithelium. We report that vitamin D3
acts constrains the organization of human breast epithelial cells induced by
estrogen and interferes with estrogen's transcriptional effects. We also report
that vitamin D3 affects breast epithelial cells' ability to manipulate collagen
fiber organization, thus altering the mechanical properties of the environment and
in turn, the organization of the epithelial cells. This is the first report of
breast epithelial cells exhibiting non-monotonic dose response to vitamin D3 in 3D
cultures, and also the first to report vitamin D3's effects on collagen fiber
organization via cells. When these observations are interpreted under the premise
of the "default state", we conclude that vitamin D3 acts as a constraint on the
development of the breast epithelium.
Thesis (Ph.D.)--Tufts University, 2019.
Submitted to the Dept. of Cell, Molecular & Developmental Biology.
Advisor: Ana Soto.
Committee: Carlos Sonnenschein, Li Zeng, and John Castellot.
Keywords: Developmental biology, Morphology, and Endocrinology.read less - ID:
- mc87q376r
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