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sion proteins [30, 31]. In some transformed breast cells, 1,25D induces apoptotic
cell death via generation of reactive oxygen species, dissipation of the mitochondrial
membrane potential and cytochrome c release in association with down regulation
of bcl-2 and activation of bax [32, 33]. The role of proteases in 1,25D mediated cell
death appears to be cell type dependent, with caspases, cathepsins and calpains
being activated under different contexts [22, 34]. Notably, 1,25D exerts additive or
synergistic effects in combination with other triggers of apoptosis, such as ionizing
radiation and chemotherapeutic agents [35–37]. Collectively, these studies indicate
that a wide variety of different signaling pathways, cell cycle and apoptotic regula-
tory proteins and proteases may contribute to the antiproliferative, prodifferentiating
and apoptotic effects of 1,25D depending on the specific cell type and/or context.

12.3.3 Emerging Role of Vitamin D in Cellular Stress Responses

Normal cells continuously sense and respond to a variety of stresses, including DNA
damage, oxidative stress, endoplasmic reticulum overload, unfolded proteins and
others. One of the major sensors of cellular stress is the tumor suppressor protein
p53, a transcription factor that integrates the response to DNA damage. Germline
mutations in p53 that disable its transcriptional activity strongly predispose to the
breast to cancer [38]. It has recently been demonstrated that p53 transcriptionally
up-regulates the human VDR via direct binding to conserved intronic p53 response
elements [39]. Other studies have implicated the p53-related family members p63
and p73 in regulation of the VDR gene [40]. Exposure of cells to DNA damaging
agents such as doxorubicin, etoposide or ionizing radiation resulted in up-regulation
of VDR expression [39, 41, 77]. Notably, VDR and p53 mediate similar biological
effects (growth arrest, apoptosis, DNA repair) via common target genes (p21, bax,
GADD45). On the p21 promoter, both independent and overlapping VDR and p53
binding sites have been characterized [42]. These studies suggest that VDR regu-
lated pathways may contribute to the tumor suppressive effects of the p53 family,
particularly those involved in cellular stress response. Other studies have implicated
c-jun in the control of VDR expression and activity in response to arsenic stress,
suggesting that VDR signaling may also protect against nongenotoxic cellular dam-
age via p53 independent pathways [43]. Further studies to clarify how p53, c-jun and
other stress responsive pathways regulate VDR signaling, and how VDR activation
in turn modulates cellular responses, are needed.

12.3.4 Preclinical Studies of VDR Agonists in Animal Models
of Breast Cancer

Although therapeutic use of 1,25D is precluded by dose-limiting calcemic toxicity,
synthetic analogs of 1,25D with low calcemic potency have provided proof of prin-
ciple that VDR agonists can inhibit growth and induce regression of mammary