 |
Richard Kremer, M.D., Ph.D., FRCP(C), Professor, Department of Medicine |
Research:
Role of vitamin D in osteoporosis, cancer progression and skeletal metastasis
My laboratory is trying to elucidate how 1,25-dihydroxyvitamin D3 1,25(OH)2D3, the active form of vitamin D, influences cell growth and differentiation in the skeleton and in cancer cells. An extension of these studies is to elaborate new therapeutic strategies with vitamin D derivatives in osteoporosis and in cancer. In normal cells, 1,25(OH)2D3 has antiproliferative and pro-differentiative actions by modulating a number of key cellular events. On the skeleton, our present strategy is to determine the nature of these changes in bone cells in vitro using mesenchymal stem cells and in vivo in animal models of osteoporosis. In cancer models our efforts are aimed at (1) understanding the mechanism of 1,25(OH)2D3 anticancer effects (2) developing new potent analogs of 1,25(OH)2D3 capable of inhibiting cell growth but with minimal side effects and (3) examining the mechanism of the anti-tumor effect of vitamin D in transgenic/knockout models of breast cancer progression and developing effective molecular strategies by targeting specific functional domains on the vitamin D receptor (VDR)/retinoid X receptor (RXR) complex (4) developing strategies for the prevention and treatment of bone metastasis.
Recent Publications:
Solomon, C., Sebag, M., White, J., Rhim, J., Kremer, R. Disruption of vitamin D receptor/retinoid X receptor heterodimer formation following ras transformation of human keratinocytes. J. Biol. Chem. 273:17573-17578, 1998.
Solomon, C., White, J.H., Kremer, R. Mitogen-activated protein kinase inhibits 1,25- dihydroxyvitamin D3-dependent signal transduction by phosphorylating human retinoid X receptor α. J. Clin. Invest. 103:1729-1735, 1999.
El Abdaimi, K., Papavasiliou, V., Rabbani, S.A., Rhim, J.S., Goltzman, D., Kremer, R. Reversal of hypercalcemia with the vitamin D analogue EB1089 in a human model of squamous cancer. Cancer Res. 59:3325-3328, 1999.
El Abdaimi, K., Dion, N., Papavasiliou, V., Cardinal, P.E., Binderup, L., Goltzman, D., Sainte Marie, L.G., Kremer, R. The vitamin D analogue EB1089 prevents skeletal metastasis and prolongs survival time in nude mice transplanted with human breast cancer cells. Cancer Research. 60:4412-4418, 2000.
Truong, N.Y., deB Edwardes, M., Papavasiliou, V., Goltzman, D., Kremer, R. Parathyroid hormone related peptide and survival of patients with cancer and hypercalcemia. Am J Med 115(2):115-121, 2003.
Duque, G., Macoritto, M., Dion, N., Ste. Marie, L.G., Kremer, R. 1,25(OH)2D3 acts as a bone forming agent in the hormone independent Senescence Accelerated Mouse (SAM-P/6) model of osteoporosis. Am. J. Physiol. Endocrinol. Metab. 288:E723-E730, 2005.
Macoritto M, Kremer R. Human retinoid Xα receptor (hRXRα) phosphorylation at serine 260 induces structural modifications of its heterodimeric complexes and alters its interactions with coactivators/corepressors. J Biol Chem. submitted.