Page 20 - Vitamin D and Cancer

1 Vitamin D: Synthesis and Catabolism 7

tumors express extremely high levels of CYP24A1, and cannot be growth-inhibited
by 1,25-(OH) D . Actually, when these CYP27B1-negative cells are exposed to
2 3
16.6 nmol 25-(OH)D , they will efficiently use up the precursor within 12 h for
3
24,25-(OH) D production and further degradation [34]. Androgen-independent
2 3
prostate cell lines also tend to express high levels of CYP24A1, whereas CYP27B1
expression is negligible (see, e.g., [57]). These few examples clearly demonstrate
an uncoupling of 1,25(OH) D action from expression of CYP24A1 during advanc-
2 3
ing malignancy: whereas, in differentiated colon and prostate cancer cells,
1,25-(OH) D will induce CYP24A1 expression, undifferentiated cells express
2 3
basally extremely high levels of CYP24A1 that can no longer be enhanced by treat-
ment with the active metabolite [38, 58]. Therefore, such basally high expression of
CYP24A1 during advanced malignancy will not permit effective treatment of patients
with vitamin D or vitamin D analogs that can be degraded via the C-24 pathway.
However, this also clearly shows that inhibition of CYP24A1 activity in tumor cells
could be of primary importance for cancer therapy. This aspect will be discussed
further in the section on epigenetic regulation of CYP24A1 (see section 1.2.5.)

1.2.3 Regulation of CYP27B1 and CYP24A1 Expression
by Sex Hormones

Although men and women suffer from similar rates of colorectal cancer deaths in
their lifetime, the age-adjusted risk for colorectal cancer is less for women than for
men [59]. This strongly indicates a protective role of female sex hormones, particu-
larly of estrogens, against colorectal cancer (see, e.g., [60, 61]). Observational
studies have further suggested that postmenopausal hormone therapy is associated
with a lower risk for colorectal cancer and a lower death rate in women [62].
A meta-analysis of studies showed a 34% reduction in the incidence of this tumor
in postmenopausal women receiving hormone replacement therapy [63]. A mecha-
nism of action for estrogens in lowering colon cancer risk is not known yet. Since
estrogen receptors are present in both normal intestinal epithelium and in colorectal
cancers, the hormone is probably protective through these receptors and resultant
post-receptor cellular activities.
While the colon cannot be considered an estrogen-dependent tissue, it must be
defined as an estrogen-responsive organ. Expression of estrogen receptor (ER)
subtypes a and b have been detected in cancer cell lines. Whereas human colon
mucosa expresses primarily the ER-b type regardless of gender [64], ER-a is
mainly expressed in the breast and the urogenital tract [65]. Both receptors bind
estrogen, but they activate promoters in different modes. Studies of breast and pros-
tate carcinogenesis suggested opposite roles for ER-a and ER-b in proliferation
and differentiation [66]. Therefore, the ER-a/ER-b ratio has been suggested as a
possible determinant of the susceptibility of a tissue to estrogen-induced carcino-
genesis: in some cells, binding of estrogen to ER-a induces cancer-promoting
effects, whereas binding to ER-b exerts a protective action. With respect to colon