Page 21 - Vitamin D and Cancer

8 H.S. Cross

cancer, the concept of a protective role of ER-b gained support recently: decreasing
levels of the receptor were reported during colonic tumorigenesis compared with
expression in the adjacent normal mucosa from the same patient [67].
Estrogens may indirectly oppose progression of malignancies by changing VDR
expression or vitamin D metabolism in colonic epithelial cells. As early as in 1986,
a study on the effect of endogenous estrogen fluctuation with respect to 25-(OH)D
3
metabolism was published [68]. This study in healthy premenopausal women sug-
gested that 25-(OH)D was metabolized predominantly to 24,25-(OH) D at low
3 2 3
estrogen, but to 1,25-(OH) D at higher serum estrogen concentrations. While this,
2 3
in 1986, primarily concerned renal synthesis of vitamin D metabolites, it was the
first suggestion that estrogen elevates CYP27B1 expression.
Liel et al. [69] reported that estrogen increased VDR activity in epithelial cells
of the gastrointestinal tract. In the colon adenocarcinoma-derived cell line Caco-2,
which is ER-b positive but negative for ER-a, we demonstrated an increase of
CYP27B1 mRNA expression and also of enzymatic activity after treatment with
17b-estradiol [70]. Based on these findings a clinical pilot trial was designed, in
which postmenopausal women with a past history of rectal adenomas were given
17b-estradiol daily for 1 month to reach premenopausal serum levels. Rectal biop-
sies were obtained at the beginning and end of trial. A predominant result was the
elevation of VDR mRNA [71]. We also observed significant induction of CYP27B1
mRNA in parallel to a decrease in COX-2 mRNA expression in those patients who
had particularly high levels of the inflammatory marker at the beginning of the trial
(Cross HS, The vitamin D system and colorectal cancer prevention. In: Vitamin D,
3rd edition. D. Feldman ed. Elsevier 2010).
To study modification of vitamin D hydroxylase activity by 17b-estradiol fur-
ther, we used a mouse model to measure actual 1,25-(OH) D synthesis and accu-
2 3
mulation in colonic mucosa. In female compared with male mice, CYP27B1
mRNA was doubled and 1,25-(OH) D concentration in the mucosa was increased
2 3
by more than 50%. This occurred in the proximal colon only and suggested that
there may be site-specific action of 17b-estradiol [127]. In this respect it is signifi-
cant, that the estrogen receptor ESR1 is more methylated (inactivated) in the human
distal than in the proximal colon [72].
There is equivocal evidence for the role of estrogen receptors (ER)-a and
(ER)-b, and therefore for estrogenic activity, during mammary tumor progression.
It has been suggested that higher ER-a expression in normal breast epithelium
increases breast cancer risk. Since 1,25-(OH) D synthesis, not only in colonocytes
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but also in mammary cells, may in part be regulated by 17b-estradiol [70], and since
epidemiological evidence points to a correlation between breast cancer incidence
and low levels of the precursor 25-(OH)D [73], evaluation of the vitamin D system
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during progression of mammary carcinogenesis could be important. When normal
breast tissue was compared with that derived from cancer patients, CYP27B1
mRNA was found in both tissues. In one study it was claimed, that expression was
higher during early malignancy similar to colonic tissue [74]. Primary cultures
established from human mammary tissue expressed CYP27B1 and were growth-
inhibited by physiologically relevant concentrations of 25-(OH)D [48], while
3