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Vitamin D3 Receptor Signaling in Mammary Gland Development and Ron-Mediated Breast Cancer

Johnson, Abby L
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1416230815

Abstract Details

2014, PhD, University of Cincinnati, Medicine: Toxicology (Environmental Health).
The vitamin D3 receptor (VDR) is an established negative regulator of mammary gland development and breast cancer as VDR null mice exhibit enhanced epithelial growth during pubertal breast development and are more susceptible to induced carcinogenesis in the mammary gland. Furthermore, the actions of VDR in the breast are largely dependent on the ligand, vitamin D3. However, it is estimated that over 1 billion people worldwide are vitamin D3 deficient or insufficient, including millions of growing children. Despite the alarming number of people with low systemic vitamin D3 levels, little is known about the repercussions of inadequate VDR signaling during critical times of growth and development, such as mammary gland development, and future disease risk. In this dissertation, we studied the cell-type specific contributions of VDR signaling in the breast during mammary gland development and the protective role of VDR in an aggressive form of breast cancer mediated by oncogenic Ron receptor tyrosine kinase overexpression. We show that VDR signaling in both mammary epithelial cells and adipocytes govern ductal outgrowth through the regulation of epithelial cell proliferation and apoptosis within terminal end buds. Mechanistically, adipocytes secrete growth regulatory cytokines such as IL-6 in response to vitamin D3 for VDR-mediated paracrine regulation of epithelial cell fate. In the context of breast cancer, oncogenic Ron is overexpressed in roughly 50% of all human cases. Ron-mediated mammary tumorigenesis requires activation of downstream ß-catenin signaling, which we demonstrate to be antagonized by vitamin D3 through the VDR. Both mammary gland hyperplasia and tumor onset were significantly delayed with VDR signaling and correlated with decreased levels of ß-catenin target genes involved in growth regulation and invasion. Moreover, vitamin D3-dependent VDR signaling increased expression of dickkopf-related protein 1, an extracellular inhibitor of canonical Wnt/ß-catenin signaling, and decreased the interaction of ß-catenin with the LEF1 binding sequence within the promoter of the established target gene, cyclin D1. Our work herein provides conclusive evidence for the functional role of vitamin D3-dependent VDR signaling within select microenvironments during mammary gland development as well as its protective role in Ron-mediated mammary tumorigenesis, suggesting the applicability of vitamin D3 interventions in public health and its clinical relevance in human breast cancer, respectively.
Shuk-Mei Ho, Ph.D. (Committee Chair)
Nira Ben-Jonathan, Ph.D. (Committee Member)
Mary Beth Genter, Ph.D. (Committee Member)
Susan Kasper, Ph.D. (Committee Member)
Susan Waltz, Ph.D. (Committee Member)
Glendon Michael Zinser, Ph.D. (Committee Member)
154 p.
Developmental Biology
vitamin D3 receptor; Ron; beta-catenin; breast cancer; mammary gland development

Recommended Citations

Citations

  • Johnson, A. L. (2014). Vitamin D3 Receptor Signaling in Mammary Gland Development and Ron-Mediated Breast Cancer [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1416230815

    APA Style (7th edition)

  • Johnson, Abby. Vitamin D3 Receptor Signaling in Mammary Gland Development and Ron-Mediated Breast Cancer. 2014. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1416230815.

    MLA Style (8th edition)

  • Johnson, Abby. "Vitamin D3 Receptor Signaling in Mammary Gland Development and Ron-Mediated Breast Cancer." Doctoral dissertation, University of Cincinnati, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1416230815

    Chicago Manual of Style (17th edition)

ucin1416230815
637
© 2014, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.
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