Page 163 - Vitamin D and Cancer

150 E. Gocek and G.P. Studzinski

cells, per se, has potential clinical significance, mechanistic studies in this system
have been largely directed to the antiproliferative effects of 1,25D on breast cancer
cells. These studies revealed that induction of apoptosis and G1 cell cycle arrest
result in inhibition of tumor cell growth in several types of breast cancer cells [20, 57, 59],
but the relationship of these biological effects to differentiation is not obvious.
Nonetheless, some hints did result from those studies, as exemplified below.
An interesting set of candidate 1,25D-target proteins was identified by pro-
teomic screening of a breast cancer cell line sensitive to 1,25D (MCF-7) and from
a subclone of these cells derived by resistance to 1,25D (MCF-7/DRES) [60], and
some of these proteins can be related to differentiation and associated phenotypic
cellular changes. Examples are Rho-GDI and Rock-DI, known to participate in the
formation of focal adhesions and stress fibers which contribute to the adhesive
epithelial phenotype and changes in cell shape [60]. Proteins previously linked to
pathways involved in 1,25D-induced differentiation such as phospho-p38, MEK2,
RAS-GAP were also noted in this screen [52]. In a tissue culture study, the JNK
pathway, also known to contribute to 1,25D-induced differentiation of colon and
myeloid cells [61], was shown to cooperate with the p38 pathway to transactivate
VDR in breast cancer cells, but this was proposed to contribute to the anti-prolifer-
ative rather than the differentiation-inducing effects of 1,25D in these cells [38].
The antiproliferative effects of 1,25D can also be explained by the reduction in
EGFR mRNA and protein, but this is seen in only some, but not all, breast cancer
cell lines [62, 63].
Another suggested link to differentiation in 1,25D-treated breast cancer cells is
that VDR and estrogen receptor (ER) pathways converge to regulate BRCA-1, thus
controlling the balance between signaling of differentiation and proliferation [64].
Since ER is important for mammary gland differentiation, studies that pursue this
concept would be very valuable, and it already appears that the overexpression of
ER and VDR is not sufficient to make ER-negative breast cancer cells responsive
to 1a,hydroxy-vitamin D , a vitamin D analog known to mediate differentiation in
5
a manner similar to 1,25D [65, 66].

7.2.3 Prostate Cancer

Similar to breast cancer cells, prostate cancer originates in hormone-dependent
epithelial cells, and, as in breast cancer cell lines, 1,25D has anti-proliferative
effects in some, but not all, established prostate cancer cell lines. The anti-proliferative
action of 1,25D is, to a variable degree, due to the induction of cell death by apop-
tosis [67] and to cell cycle arrest [68], but to what extent these are associated with
differentiation is uncertain.
The evidence of prostate cancer cell differentiation includes the release of pros-
tate specific antigen (PSA) from cells treated with a differentiating agent such as
1,25D [69–71]. This can be useful in cultured cells, but in patients the increasing
PSA levels suggest progressive disease, making it difficult to acquire data on the