Vitamin D Hormone Action in the Endocrine Tissue: Implications for Prostate and Breast Carcinoma

Caleb Killer, Jungmi Ahn, Sulgi Park, Bandana Chatterjee

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

The vitamin D receptor (VDR), which regulates a plethora of genes with diverse functions for transcriptional activation or repression, is expressed in many extraskeletal tissues including endocrine tissues such as prostate and breast. CYP27B1 activity mediates local synthesis of the hormonally active 1α, 25-dihydroxyvitamin D 3 (calcitriol) from circulating 25-hydroxyvitamin D 3 , although kidneys are the primary site of calcitriol production. VDR, upon calcitriol binding, undergoes conformational change and heterodimerization with the retinoid X receptor (RXR) that lead to association of the VDR/RXR complex with vitamin D-responsive DNA elements along the genome. Search for clinically viable new VDR agonists has continued utilizing computer modeling information on energetically favorable modes of agonist interaction with VDR’s ligand-binding domain. End results of vitamin D/VDR signaling constitute diverse extraskeletal effects including cell cycle arrest, differentiation, and apoptosis. Growth inhibition of malignant prostate and breast cells by calcitriol has been extensively documented in cell culture and animal models. Although monotherapy with calcitriol or its analog did not show clear clinical benefits, daily vitamin D supplementation may have chemoprevention effect on low-grade prostate cancer, revealed from small-scale pilot studies. Inecalcitol, a highly potent VDR agonist with markedly reduced calcemic toxicity, is currently under clinical evaluation in conjunction with conventional chemotherapy against metastatic castration-resistant prostate cancer. Our results revealed an inhibitory interplay of the calcitriol-VDR axis with androgen receptor (AR), the key driver of prostate cancer, since androgen treatment of prostate cancer cells prevented calcitriol-regulated induction of both AR and the calcitriol-inactivating 24-hydroxylase, i.e., CYP24A1. Further exploration of an androgen/vitamin D combination protocol may unveil a new route to prostate cancer inhibition. Insights into epigenetic regulators of vitamin D/VDR signaling and effectors of the VDR pathway may be leveraged in the search for clinically viable drugs to target neoplastic lesions in prostate, breast, and other tissues.

Original languageEnglish (US)
Title of host publicationContemporary Endocrinology
PublisherHumana Press
Pages77-101
Number of pages25
DOIs
StatePublished - Jan 1 2018

Publication series

NameContemporary Endocrinology
ISSN (Print)2523-3785
ISSN (Electronic)2523-3793

Keywords

  • Androgen receptor
  • Aromatase
  • Breast cancer
  • Calcitriol
  • Clinical trials
  • Estrogen receptor
  • Prostate cancer
  • Transcription regulation
  • Vitamin D receptor

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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  • Cite this

    Killer, C., Ahn, J., Park, S., & Chatterjee, B. (2018). Vitamin D Hormone Action in the Endocrine Tissue: Implications for Prostate and Breast Carcinoma. In Contemporary Endocrinology (pp. 77-101). (Contemporary Endocrinology). Humana Press. https://doi.org/10.1007/978-3-319-73742-3_4