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.