Antiproliferative effects of calcitriol were mainly detected in breast carcinoma lineages exposed in vitro to high hormone concentrations, which is associated with hypercalcemia in human beings. To test the hypothesis that intra-tumoral administration of calcitriol would allow higher tissue concentration of the hormone and activation of the genomic pathway, a tumorgraft model, that more closely reproduces the molecular characteristics of the primary tumor, was established. Freshly collected breast cancer samples from 14 patients were ortothopically grafted in nude mice. On the sixth week after xenografting, no palpable nodules were detected in mice implanted with 6 samples. Intra-tumoral weekly injections of calcitriol 0.06 μg (dose that allow peak serum calcitriol levels in the predicted therapeutic range) or vehicle were initiated and maintained for six weeks in mice xenografted with another 8 samples. Tumorgraft proliferation, apoptosis and target genes expression were evaluated through immnunohistochemistry reactions or RT-PCR. At the end of the experiment, tumorgrafts originated from three samples were available for analysis. VDR expression was detected in these samples as well as a trend towards higher expression of CYP24A1 mRNA (10-18 fold) in calcitriol treated samples, indicating that the genomic pathway was induced. A high proliferative index, evaluated by Ki67 expression, was observed, however, neither differences in the expression of proliferation markers (BrdU incorporation, Ki67 and CDKN1B expression) nor in apoptosis markers (cleaved caspase 3 and BCL2 expression) between vehicle and calcitriol treated tumorgrafts was detected. Additionally, no difference between groups was noticed for the expression of CDKN1A mRNA. In summary, in this small study, calcitriol antitumoral effects were not observed in tumorgrafts, established from highly proliferative breast cancer samples. This preclinical model in conjunction with pharmacokinetic calcitriol determinations might contribute to clarify the hormone effects in breast cancer.
Citation Format: Maria Lucia Hirata Katayama, Victor Celso N. Fonseca-Filho, Eduardo Carneiro Lyra, Durvanei Augusto Maria, Ricardo Alves Basso, Suely Nonogaki, Juliana Mariotti Guerra, Simone Maistro, João Carlos Sampaio Goes, Maria Aparecida A. Koike Folgueira. Calcitriol effects on breast cancer tumorgrafts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3115. doi:10.1158/1538-7445.AM2014-3115