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Incidence of breast cancer and mortality rate considerably vary worldwide and reveal a geographic pattern. The lowest rates of breast cancer generally occur in countries close the equator. With increasing latitude reported breast cancer incidence and mortality rates also increase. A negative correlation between available sunlight and breast cancer death rates has been shown. Because sunlight exposure is a measure of vitamin D produced in the skin, it has been hypothesized that vitamin D formed in the skin may reduce the risk of breast cancer (1-3).
Breast cancer is the most frequent cause of cancer death in women in the western world. Many studies have tried to identify the casual factors responsible for the uncontrolled growth of the tumor cells. A variety of biochemical and genetic changes have been identified in breast carcinomas and have been found to be related to breast cancer growth. However, especially because of the heterogeneity of the disease on the clinical, biologic and genetic levels, the exact mechanism of breast cancer development and progression is still unclear. During the last 15 years, it has become evident that 1,25-dihydroxyvitamin D3 ( 1,25(OH)2D3), the biologically most active form of vitamin D3, exerts effects on a variety of tissues which are apparently unrelated to calcium homeostasis. 1,25 (OH)2D3 has been shown to induce cellular differentiation and inhibit proliferation of hematopoietic cells and cancer cells. In addition, studies with animal cancer models have shown that 1,25 (OH)2D3 application can prolong the survival of leukemic mice and suppress the growth of tumors of different origins including breast (4,5).
These newly discovered properties suggest a possible role of the hormone in the treatment of cancer. However, a major drawback for a clinical application is that high doses are needed. These doses produce serum levels of 1,25(OH)2D3 far above the physiologic level, which may lead to hypercalcemia. Many investigators have tried to change the 1,25 (OH)2D3 molecule in order to retain its ant proliferative and differentiation-inducing activity combined with a reduced effect on calcium and bone metabolism. This strategy has resulted in new synthetic vitamin D3 analogs with clinical potential (6-8).
The expression of the vitamin D receptor (VDR) in breast cancer was first demonstrated in the human breast cancer cell line MCF-7 (9). Further studies have extended this finding even to surgically obtained normal breast and breast tumor tissue (10).
The VDR is expressed in about 80% of human breast tumor specimens. The VDR status is not correlated to the expression of other steroid hormone receptors (estrogen receptor, progesterone receptor) (11-30) or to the clinical indices (age, menopausal status, T-stage, histology, lymph node involvement) including overall survival (12-31). Nevertheless, two studies reported that the VDR status correlated positively with the disease-free interval (14-31).
The steroid hormone responsiveness is directly proportional to the number of corresponding receptors. Regulation of the number of VDR may affect the cellular responsiveness to 1,25 (OH)2D3. In several different systems including MCF-7 and T47-D breast cancer cells, upregulation of the VDR by 1,25 (OH)2D3 itself (homologous upregulation) and by hormones (estradiol) and growth factors (epidermal growth factor (EGF), insulin, insulin-like growth factor-1 (IGF-1)) has been demonstrated (heterologous upregulation) (2, 32-37). Because VDR mediates the biological effects of calcitriol and analogs on differentiation and proliferation in target cells, VDR upregulation may indicate an increased sensitivity of breast cancer to endogenously or therapeutically applied calcitriol. Thus, a relationship between VDR level and growth inhibition has been suggested for breast cancer cells (38,39). Nevertheless, the presence of a functional VDR is not always combined with a growth-inhibitory response of 1,25 (OH)2D3. A lack of growth inhibition by 1,25 (OH)2D3 independent of the status of functional VDR has been demonstrated in breast cancer cells (40,41). The underlying mechanism of this VDR-independent resistance to growth inhibition is unknown.
The first studies on the effect of 1,25 (OH)2D3 on breast cancer cells showed a biphasic growth response of the estrogen receptor-positive T47-D human breast tumor cell line. At low concentrations (10-11 M), a stimulation of cell growth was observed (10, 42, 43). This growth-inhibitory effect of 1,25 (OH)2D3 was confirmed in other breast tumor cell lines and shown to be independent of the estrogen receptor status (44,45). In the growth inhibited breast cancer cells 1,25 (OH)2D3 and 1,25 (OH)2D3 analogs caused an increase of the number of cells in the GO/GI and occasionally in the G2 phase together with a decrease of the number of cells in the S phase (40,44,46-49) indicating a cell cycle block in the GO/GI phase. Apoptosis (programmed cell death), is an asynchronous cellular process with cytoplasmic and nuclear condensation, disruption of the cytoskeleton and condensation of intermediate filaments around the nucleus and is related to the cell cycle (50). Induction of apoptosis can be a possible way in which 1,25 (OH)2D3 inhibits tumor cell growth. Recently it has been shown that 1,25 (OH)2D3 induces apoptosis in various tumor cells (40,49,51,52). A central role for apoptosis in the action of 1,25 (OH)2D3 is uncertain because growth inhibition of several breast cancer cells appeared to be independent of apoptosis (40). Thus, the growth stimulation of MCF-7 cells, that were growth inhibited by 1,25 (OH)2D3, after removal of 1,25 (OH)2D3 indicates independence of growth inhibition from apoptosis (53). Possibly in these latter cases induction of differentiation is more prominent. Treatment of breast cancer cells with 1,25 (OH)2D3 resulted in morphologic changes, which may resemble a more differentiated status of the cells (43,54,55). Induction of differentiation was recently shown in several breast cancer cells (40). The results of these studies suggest that induction of differentiation and growth inhibition are two independent processes. The various synthetic vitamin D3 analogs have been shown to be more potent than 1,25 (OH)2D3 in the growth inhibition of several cancer cell types, whereas their in vivo calcemic activity was similar or even reduced compared with 1,25 (OH)2D3.
Mammary tumors can be induced in rats by oral administration of the carcinogens N-nitroso-N-methylurea (NMU) or 7,12-dimethylben(a)anthracene (DMBA). Application of 1,25 (OH)2D3 resulted in an inhibition of the growth of NMU- (31,56) and DMBA-induced rat mammary tumors (57,58), whereas Noguchi et al. (59) did not find an effect of 1,25 (OH)2D3 on the incidence and growth of DMBA- induced rat mammary tumors. To achieve tumor suppression, high doses of 1,25 (OH)2D3 about 0,5 ug/kg BW) were needed with the subsequent development of hypercalcemia and weight loss. Thus, synthetic vitamin D3 analogs with low in vivo calcemic activity have been developed. Only a few analogs have been evaluated in vivo for their potential use in the treatment of breast cancer. To date, two clinical studies on the effect of vitamin D3 analogs on cancer growth in humans have been reported. Topical application of calcipotriol (MC903) in a small group of patients with locally advanced or cutaneous metastatic breast cancer showed a reduction in the size of treated lesions in 4 of 14 patients (60), whereas another study could not confirm this observation (61). In a phase I trial the analog EB1089 is being examined in advanced breast cancer, but no detailed analyses have been published.
The antiestrogen tamoxifen is the most widely used endocrine agent in the treatment of breast cancer (62). A major problem of tamoxifen therapy is that in case of response, the tumor almost inevitably progresses to a tamoxifen-resistant state during prolonged therapy. Furthermore, long-term tamoxifen therapy has been linked to an increased risk of endometrial cancer. Therefore, despite the efficacy of tamoxifen for breast cancer, alternative additional endocrine therapies are needed. Thus, several studies have focused on possible future combination treatment with 1,25 (OH)2D3 and 1,25 (OH)2D3 analogs in estrogen receptor-positive and –negative breast cancer. A synergistic antiproliferative effect of submaximum dosages of the vitamin D analog, 22-oxacalcitriol, and tamoxifen in breast cancer cells has been described in vitro and in vivo (63).
Thus the combined treatment with 1,25 (OH)2D3 and tamoxifen resulted in stronger growth inhibition of MCF-7 cells than treatment with either compound alone (53). With a number of vitamin D3 analogs a similar effect was observed (37). In combination with tamoxifen the cells were more sensitive to the antiproliferative action of 1,25 (OH)2D3 and the analogs (37). The ability of tamoxifen to reduce the total tumor burden of rats treated with the carcinogen NMU is significantly enhanced by a combination of the vitamin D3 analog, Ro24-5531, with low doses of tamoxifen (64). Thus, implications for the use of vitamin D analogs not only in treatment but also in the prevention of breast cancer have been indicated. Vitamin A-derivatives like fenretinide are currently being tested in clinical trials as preventive agents against recurrence of breast cancer, and animal studies point to a potential use of these compounds as therapeutic agents for breast cancer (65). A combination therapy of retinoic acid and 1,25 (OH)2D3 showed a synergistic growth inhibition of breast cancer cells (66). Furthermore, combinations with vitamin D3 compounds and cytotoxic drugs (TNF, GMCSF, Adriamycin, 5-FU, Carboplatin, Cisplatin) have been studied (45,57,67-69). The data on combinations of 1,25 (OH)2D3 and 1,25 (OH)2D3 analogs with various other anticancer compounds are promising and justify further analyses. For example, the development of effective combination therapies may result in better response rates and lower dosages combined with a reduced risk of negative side-effects.
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