Vitamin D effects on cell proliferation and gene expression profile of breast cancer post-menopausal patients

• Grant number: 07/04799-2
• Support Opportunities: Regular Research Grants
• Duration: January 01, 2008 - December 31, 2010
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Maria Aparecida Azevedo Koike Folgueira
• Grantee: Maria Aparecida Azevedo Koike Folgueira
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

An inverse relationship between decreased sunlight exposure and diminished 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 1,25-(OH)2D3 levels occurs in early stage breast cancer patients as compared those with bone metastatic disease.Another possible link between the vitamin D pathway and breast cancer was recently reported as an amplification of CYP24, 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 shown in breast cancer cell lines and breast cancer specimens, however, positive as well as negative association between VDR status and prognosis of breast cancer were found.The mechanism underlying 1,25(OH)2D3 induced G0/G1 phase growth arrest has been mainly studied in breast carcinoma cells and involves molecules like the retinoblastoma protein (pRb), cyclins D and E, and cyclin dependent kinase inhibitors (Cdki), p21WAF1/CIP1 and p27KIP1 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 β, TGFβ (which can inhibit the proliferation of epithelial cells), TGFβ 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. 1,25(OH)2D3 has also been linked to the regulation of the early response genes, whose products are transcriptional factors that modulate cell growth, differentiation and apoptosis, as c-myc in breast cancer cells as well as members of the fos/jun families, in leukemia and colon cancer cells. Most of this data results from studies in cell cultures where epithelial-mesenchimal relation is not evaluated and using vitamin D supra-physiological concentrations.Hence, although enough data suggest this antiproliferative effect of vitamin D in breast cancer cell lines and animal models, there is much uncertainty about its action in human beings. Vitamin D supplementation in post-menopausal women was not shown to reduce colorectal or breast cancer incidence. Otherwise, some authors have demonstrated that vitamin d analogs may reduce skin lesions of breast cancer and when associated to docetaxel may improve overall survival of prostate cancer patients.Our first aim was to evaluate tumor proliferation (as determined by Ki67 expression), 1,25(OH)2D3 serum concentration, tumor expression of target genes as 24 hydroxylase, p21, p27, IGFBP3, and tumor gene expression, before and after calcitriol supplementation to post-menopausal breast cancer patients. Tumor specimens and blood samples will be collected during tumor biopsy and during surgery for tumor resection.Another aim was to evaluate the expression of target genes and gene expression on slices of breast cancer samples treated in vitro with physiological as well as supra-physiological concentrations of 1,25(OH)2D3. Tumor slices preserve epithelial-mesenchimal interactions and also allow the comparison of different concentrations on gene expression. (AU)

Scientific publications

(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)

MILANI, CINTIA; HIRATA KATAYAMA, MARIA LUCIA; DE LYRA, EDUARDO CARNEIRO; WELSH, JOELLEN; CAMPOS, LAURA TOJEIRO; MITZI BRENTANI, M.; MACIEL, MARIA DO SOCORRO; ROELA, ROSIMEIRE APARECIDA; DEL VALLE, PAULO ROBERTO; GUEDES SAMPAIO GOES, JOAO CARLOS; et al. Transcriptional effects of 1,25 dihydroxyvitamin D-3 physiological and supra-physiological concentrations in breast cancer organotypic culture. BMC CANCER, v. 13, MAR 15 2013. (07/04799-2, 09/10088-7)