In the past decade there has been increasing interest in 1,25(OH)2D3 and its role in breast cancer. Several studies report an inverse relationship between Vitamin D intake, sunlight exposure or serum 25(OH)D3 and breast cancer incidence. However, there are questions as to the role of the Vitamin D receptors, Vitamin D Receptor (VDR) and Membrane Associated, Rapid Response Steroid-Binding (1,25D3-MARRS) protein in causing these effects. Our study explored whether the level of 1,25D3-MARRS protein expression affects the anti-proliferative effects of 1,25(OH)2D3 in MCF-7 breast cancer cells in mice. Forty-two mice were given an injection of MCF-7 cells expressing either normal or approximately 50% of normal 1,25(OH)2D3 MARRS protein, which was achieved using ribozyme knockdown. Mice were injected with either 0.05[mu]g 1,25(OH)2D3 or saline every second day over 36 days. 1,25(OH)2D3 caused a significant reduction in tumor weight while decreased expression of 1,25D3-MARRS protein significantly increased sensitivity of tumor volume to 1,25(OH)2D 3.