Page 162 - Vitamin D and Cancer

7 Induction of Differentiation in Cancer Cells by Vitamin D 149

may be augmented by direct VDR/b-catenin interaction [48]. Since b-catenin/T-cell
transcription factor 4 (TCF-4) complex is the nuclear effector of the Wnt growth-
signaling pathway, responsible for the expression of c-myc and other growth pro-
moting genes [49], the repressive effects of 1,25D on the growth of colon cancer
cells may be explained by the ability of 1,25D to regulate the expression of VDR,
E-cadherin, and the activity of the b-catenin/TCF pathway, as illustrated in
Fig. 7.1.
In addition to protein–protein complex formation with b-catenin, VDR has also
been reported to interact with the transcription factor – Specificity protein 1 (Sp1) in
SW 620 human cancer cells, and thus induce the expression of p27/Kip1 inhibitor of
the cell cycle [50]. However, it is not clear precisely how this is achieved, given the
ubiquitous nature of Sp1 binding sites in gene promoters. Nonetheless, the direct
binding of VDR to other proteins, which may be ligand-independent, is an area that
deserves further study, and has been reported to occur in cell types other than colon
carcinoma, such as osteoblastic cells and myeloid leukemia, as discussed later.

7.2.2 Breast Cancer

The induction of differentiation of breast cancer cell lines by 1,25D and the role of
1,25D in normal development of rodent mammary tissue are well established. For
instance, studies of VDR knockout mice in the Welsh laboratory have shown that
1,25D participates in the growth inhibition of the normal mammary gland [51].
Further, the disruption of 1,25D/VDR signaling leads to distorted morphology of
murine mammary gland with duct abnormalities and increased numbers of preneo-
plastic lesions, suggesting that 1,25D-liganded VDR serves to maintain differentiation
of normal mammary epithelium [52].
Induction of differentiation of breast cancer cells by 1,25D can be demonstrated
by b-casein production [53], or by a change in overall cell size and shape, associated
with changed cytoarchitecture of actin filaments and microtubules in MDA-MB-453
cells [54]. Treatment of these cells with 1,25D resulted in accumulation of integrins,
paxillin, and focal adhesion kinase, as well as their phosphorylation. In contrast, the
mesenchymal marker N-cadherin and the myoepithelial marker P-cadherin were
down-regulated, suggesting that 1,25D reverses the myoepithelial features associ-
ated with the aggressive forms of human breast cancer. However, it is to be noted
that not all breast cancer cell lines respond to 1,25D. In many cases this can be
attributed to the lack of or low VDR expression or function [55, 56], but it may also
be due to alterations in 1,25D-metabolizing enzymes which can reduce the levels
of 1,25D below its effective concentration [57].
Among the breast cancer cell lines that do respond to 1,25D a range of phenotype
alterations has been reported [58], emphasizing that the mechanistic basis for the
differentiating effects of 1,25D in the breast cancer cell system will be very complex.
Together with the uncertainty about whether induced differentiation of breast cancer