Sequential Versus Combined Treatment of Human Breast Cancer Cells with Antiestrogens and the Vitamin D Analogue EB1089 and Evaluation of Predictive Markers for Vitamin D Treatment

Abstract

Development of resistance to antihormonal therapy is a major problem in the treatment of breast cancer patients. Metastatic tumors, which progress after a period of response to treatment, often respond to second line endocrine treatment, but eventually develop estrogen independent growth. Vitamin D analogues are promising new drugs, using alternative mechanisms to inhibit growth of breast cancer cells. The sensitivity to antiestrogens and vitamin D analogues has been proposed to be inverse, indicating that the sensitivity to vitamin D analogues might increase after development of antiestrogen resistance and vice versa. In this study, the inverse sensitivity between antiestrogens and the vitamin D analogue EB1089 was examined in antiestrogen and vitamin D resistant breast cancer cell lines. The majority of the investigated antiestrogen resistant cell lines had increased sensitivity to treatment with the vitamin D analogue EB1089. In addition, growth of a vitamin D resistant cell line was more inhibited by the pure antiestrogen ICI 182,780 than the growth of the parental cells, indicating that the compounds may be used sequentially. An association between the expression level of the vitamin D receptor (VDR) and EB1089 sensitivity was observed, suggesting that VDR is a possible predictive marker for response to vitamin D treatment. Valuation of Bcl-2 gene expression may be useful in combination with VDR to predict the outcome of treatment with EB1089. Furthermore, we observed a synergistic growth inhibition and an abrogated development of resistance upon combined treatment with ICI 182,780 and EB1089. Therefore, antiestrogens and vitamin D analogues may also be used as combined treatment for breast cancer patients in the future.

Breast cancer cells with acquired antiestrogen resistance are sensitized to cisplatin-induced cell death

“…It has previously been shown that Bcl-2 protein expression is lower in the majority of antiestrogen-resistant MCF-7 cell lines compared with parental MCF-7 cells (32,33). Figure 5A shows that the Bcl-2 protein level was lower in all eight antiestrogen-resistant cell lines investigated here compared with the MCF-7 cell line.…”

QW-1624F2-2, a synthetic analogue of 1,25-dihydroxyvitamin D3, enhances the response to other deltanoids and suppresses the invasiveness of human metastatic breast tumor cells

“…Our studies complement the recent report by Miettinen et al (62) where CYP24 inhibition by VID400, a ketoconazole-like compound, enhanced the growth inhibitory effects of 1,25(OH) 2 D 3 in ovarian cancer cells. Similarly, Christensen et al (63) have reported that combined treatment of an antiestrogen with a 1,25(OH) 2 D 3 analogue was synergistic, abrogating the development of resistance in MCF-7 breast tumor cells in vitro.…”

Vitamin D as a regulator of steroidogenic enzymes

“…Cell culture based experiments and laboratory animal experiments has clearly shown that 1α,25-dihydroxyvitamin D 3 is able to decrase the production and action of estrogens in breast cancer models, and also the growth of breast cancer xenotumors 70,[72][73][74][75]80 . Based on these findings, vitamin D or analogs has been proposed to be of potential use as an anti-cancer agent 76,[81][82][83][84] and a large number of clinical trials (e.g. ClinicalTrials.gov identifiers NCT00656019, NCT01472445, NCT01965522, NCT01948128, NCT01787409, and NCT01097278) are currently being conducted using vitamin D or analogs in different settings to investigate the potential use in the prevention or treatment of breast cancer.…”