The potential therapeutic benefits of vitamin D in the treatment of estrogen receptor positive breast cancer

Aruna V Krishnan, Srilatha Swami, David Feldman, Aruna V Krishnan, Srilatha Swami, David Feldman

Abstract

Calcitriol (1,25-dihydroxyvitamin D(3)), the hormonally active form of vitamin D, inhibits the growth of many malignant cells including breast cancer (BCa) cells. The mechanisms of calcitriol anticancer actions include cell cycle arrest, stimulation of apoptosis and inhibition of invasion, metastasis and angiogenesis. In addition we have discovered new pathways of calcitriol action that are especially relevant in inhibiting the growth of estrogen receptor positive (ER+) BCa cells. Calcitriol suppresses COX-2 expression and increases that of 15-PGDH thereby reducing the levels of inflammatory prostaglandins (PGs). Our in vitro and in vivo studies show that calcitriol decreases the expression of aromatase, the enzyme that catalyzes estrogen synthesis selectively in BCa cells and in the mammary adipose tissue surrounding BCa, by a direct repression of aromatase transcription via promoter II as well as an indirect effect due to the reduction in the levels of PGs, which are major stimulator of aromatase transcription through promoter II. Calcitriol down-regulates the expression of ERα and thereby attenuates estrogen signaling in BCa cells including the proliferative stimulus provided by estrogens. Thus the inhibition of estrogen synthesis and signaling by calcitriol and its anti-inflammatory actions will play an important role in inhibiting ER+BCa. We hypothesize that dietary vitamin D would exhibit similar anticancer activity due to the presence of the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) in breast cells ensuring conversion of circulating 25-hydroxyvitamin D to calcitriol locally within the breast micro-environment where it can act in a paracrine manner to inhibit BCa growth. Cell culture and in vivo data in mice strongly suggest that calcitriol and dietary vitamin D would play a beneficial role in the prevention and/or treatment of ER+BCa in women.

Copyright © 2012 Elsevier Inc. All rights reserved.

Figures

Fig 1. Inhibition of estrogen synthesis and…
Fig 1. Inhibition of estrogen synthesis and signaling by calcitriol
Panel A. Cox-2, prostaglandin and aromatase regulation of estrogen synthesis and signaling in the breast microenvironment leading to increased BCa proliferation. Panel B. The ability of calcitriol to inhibit the prostaglandin and estrogen signaling pathways and thereby inhibit BCa proliferation. Calcitriol decreases the expression of aromatase, the enzyme that converts androgenic precursors to estrogens both in the cancerous breast epithelial cells (breast cancer, BCa cell) and in the breast adipose fibroblasts (BAF) in the stroma surrounding the tumor by a direct transcriptional repression of the aromatase promoter II. Calcitriol also suppresses the expression of COX-2 in the BCa cells and BAFs, thereby reducing the levels of PGE2. PGE2 stimulates proliferation, angiogenesis and other pro-carcinogenic pathways and inhibits apoptosis. PGE2 is also a major stimulator of aromatase transcription via promoter II. The decrease in PGE2 therefore provides a second, indirect mechanism for aromatase repression by calcitriol both in the BCa cells and the surrounding BAFs leading to a decrease in estrogen synthesis in the BCa microenvironment. Calcitriol also down-regulates ERα levels by the direct transcriptional repression of the ERα promoter. The down-regulation of both the hormone (E2) and receptor (ERα) levels by calcitriol thus significantly reduces the important proliferative stimulus of estrogens on ER+ BCa cells. Calcitriol also inhibits BCa proliferation by additional pathways including cell cycle arrest, proapoptotic and pro-differentiation actions, anti-inflammation, etc. which are active in both ER+ and ER-negative BCa cells. AA = arachidonic acid, E2 = estradiol, ERα = estrogen receptor α, PGE2 = prostaglandin E2, T = testosterone. (The figure has been adapted from a figure in [41] and used with permission).
Fig 1. Inhibition of estrogen synthesis and…
Fig 1. Inhibition of estrogen synthesis and signaling by calcitriol
Panel A. Cox-2, prostaglandin and aromatase regulation of estrogen synthesis and signaling in the breast microenvironment leading to increased BCa proliferation. Panel B. The ability of calcitriol to inhibit the prostaglandin and estrogen signaling pathways and thereby inhibit BCa proliferation. Calcitriol decreases the expression of aromatase, the enzyme that converts androgenic precursors to estrogens both in the cancerous breast epithelial cells (breast cancer, BCa cell) and in the breast adipose fibroblasts (BAF) in the stroma surrounding the tumor by a direct transcriptional repression of the aromatase promoter II. Calcitriol also suppresses the expression of COX-2 in the BCa cells and BAFs, thereby reducing the levels of PGE2. PGE2 stimulates proliferation, angiogenesis and other pro-carcinogenic pathways and inhibits apoptosis. PGE2 is also a major stimulator of aromatase transcription via promoter II. The decrease in PGE2 therefore provides a second, indirect mechanism for aromatase repression by calcitriol both in the BCa cells and the surrounding BAFs leading to a decrease in estrogen synthesis in the BCa microenvironment. Calcitriol also down-regulates ERα levels by the direct transcriptional repression of the ERα promoter. The down-regulation of both the hormone (E2) and receptor (ERα) levels by calcitriol thus significantly reduces the important proliferative stimulus of estrogens on ER+ BCa cells. Calcitriol also inhibits BCa proliferation by additional pathways including cell cycle arrest, proapoptotic and pro-differentiation actions, anti-inflammation, etc. which are active in both ER+ and ER-negative BCa cells. AA = arachidonic acid, E2 = estradiol, ERα = estrogen receptor α, PGE2 = prostaglandin E2, T = testosterone. (The figure has been adapted from a figure in [41] and used with permission).

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