Calcitriol (1,25-dihydroxyvitamin D(3)), the hormonally active metabolite of
vitamin D, exerts many anticancer effects in
breast cancer (BCa) cells. We have previously shown using cell culture models that
calcitriol acts as a selective
aromatase modulator (SAM) and inhibits
estrogen synthesis and signaling in BCa cells. We have now examined
calcitriol effects in vivo on
aromatase expression,
estrogen signaling, and
tumor growth when used alone and in combination with
aromatase inhibitors (AIs). In immunocompromised mice bearing MCF-7 xenografts, increasing doses of
calcitriol exhibited significant
tumor inhibitory effects (~50% to 70% decrease in
tumor volume). At the suboptimal doses tested,
anastrozole and
letrozole also caused significant
tumor shrinkage when used individually. Although the combinations of
calcitriol and the AIs caused a statistically significant increase in
tumor inhibition in comparison to the single agents, the cooperative interaction between these agents appeared to be minimal at the doses tested.
Calcitriol decreased
aromatase expression in the xenograft
tumors. Importantly,
calcitriol also acted as a SAM in the mouse, decreasing
aromatase expression in the mammary adipose tissue, while increasing it in bone marrow cells and not altering it in the ovaries and uteri. As a result,
calcitriol significantly reduced
estrogen levels in the xenograft
tumors and surrounding breast adipose tissue. In addition,
calcitriol inhibited
estrogen signaling by decreasing
tumor ERα levels. Changes in
tumor gene expression revealed the suppressive effects of
calcitriol on inflammatory and growth signaling pathways and demonstrated cooperative interactions between
calcitriol and AIs to modulate gene expression. We hypothesize that cumulatively these
calcitriol actions would contribute to a beneficial effect when
calcitriol is combined with an AI in the treatment of BCa.