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Proliferation and expression of target genes in breast cancer xenografts from post menopausal patients exposed to intratumoral calcitriol

Grant number: 11/09103-1
Support type:Regular Research Grants
Duration: August 01, 2011 - January 31, 2014
Field of knowledge:Health Sciences - Medicine
Principal researcher:Maria Aparecida Azevedo Koike Folgueira
Grantee:Maria Aparecida Azevedo Koike Folgueira
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. researchers:Maria Lucia Hirata Katayama


A relationship between decreased sunlight exposure and reduced vitamin D production on the skin and higher breast cancer incidence and mortality was previously suggested. According to this hypothesis, it was reported that women affected by breast cancer show lower 1,25(OH)2D3 or 25(OH)D3 serum levels than unaffected ones. It was also shown that higher serum 25(OH)D3 or 1,25(OH)2D3 levels occur in early stage breast cancer patients as compared those with bone metastatic disease and 25(OH)D3 deficiency is associated with poor prognosis.Another possible link between the vitamin D pathway and breast cancer was reported as an amplification of CYP24A1, that encodes vitamin D 24-hydroxylase, an enzyme responsible for 1,25-(OH)2D3 degradation. On the other hand, 1a-hydroxylase, responsible for 25-(OH)D3 activation, was detected in normal human breast, as well as in breast carcinoma samples, indicating that both normal and cancerous tissues could be capable of 25-(OH)D3-1a-hydroxylation and local synthesis of 1,25-(OH)2D3. Receptors for 1,25-(OH)2D3 were also shown in breast cancer cell lines and breast cancer specimens. Hence, the vitamin D pathway may be a possible anti-tumoral target.The mechanism underlying 1,25(OH)2D3 induced G0/G1 phase growth arrest has been mainly studied in breast carcinoma cells and involves transcription regulation of molecules like cyclins D and E, and cyclin dependent kinase inhibitors as p21WAF1/CIP1 (CDKN1A) and p27KIP1 (CDKN1B) as the downstream targets of the hormone. It was also reported that 1,25(OH)2D3 antiproliferative effects in breast cancer cells could be mediated by the up-regulation of transforming growth factor ², TGF² (which can inhibit the proliferation of epithelial cells), TGF² receptors and insulin-like growth factor binding protein-3 (IGFBP-3), which regulates the availability of insulin-like growth factor (IGF), an important mitogen for normal mammary epithelial and breast cancer cells. Most of this data results from studies in breast cancer cell culture, where epithelial-mesenchimal relation is not evaluated, employing vitamin D supra-physiological concentrations of 10-100nM, associated with hypercalcemia in human beings.Recent data from our group indicate that calcitriol supplementation to post-menopausal breast cancer patients may reduce tumor proliferation. In addition, there is evidence that vitamin D analog may be of some clinical benefit when topically administered to patients with metastatic breast cancer.Therefore, our goal is to evaluate the effects of calcitriol on the proliferation, apoptosis and gene expression of breast cancer xenografts. To this end, breast cancer samples will be transplanted in female nude mice and tumor development will be observed in treated and untreated animals. Fresh tumor slices may help reduce the interference associated with studies employing cancer cells lines maintained in culture for long periods of time. In addition, tumor slices preserve the epithelial mesenchymal interactions, allowing an integrated analysis of a certain kind of treatment. A group of mice will be receive intratumoral injections of calcitriol (high concentration, which however may be safely administered to human beings, in accordance with phase I clinical studies) in contrast with mice from the control group. This approach may help us to evaluate whether calcitriol may have anti-tumoral effects in vivo. (AU)

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FONSECA-FILHO, V. C. N.; KATAYAMA, M. L. H.; LYRA, E. C.; MARIA, D. A.; BASSO, R. A.; NONOGAKI, S.; GUERRA, J. M.; MAISTRO, S.; GOES, J. C. G. S.; FOLGUEIRA, M. A. A. K.. Orthotopic tumorgrafts in nude mice as a model to evaluate calcitriol effects in breast cancer. Brazilian Journal of Biology, v. 77, n. 4, p. 856-867, . (11/09103-1)

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