Interactions between Vitamin D, Breast Cancer and Mesenchymal Stem Cells: In Vitro And in Vivo Perspectives

Abstract

The active metabolite of vitamin D, 1α25-Dihydroxy vitamin D3 (1α25 (OH)2D3) is known to be an inhibitor of breast cancer cell growth. However, actions of its precursors 25(OH)D and Vitamin D have not been fully investigated. Mesenchymal stem cells (MSCs) have been identified as regulators of cancer growth, however the effects of 1α25 (OH)2D3 on these actions is unknown. MDA-MB231 and MCF7 cells were evaluated for direct effects of 1α25 (OH)2D3, 25(OH) D3 and vitamin D3 on their proliferation and invasiveness. The effect of 1α25 (OH)2D3 on expressed factors in MSC conditioned media (CM) was assessed by microarray. Treatment of MDA-MB-231 and MCF7 cells with vitamin D3 did not inhibit cell growth but increased apoptosis and decreased invasiveness. Gene expression of CYP24 did not change indicating no activation of vitamin D receptor (VDR) signalling. Treatment of MDA-MB-231 and MCF7 cells with MSCs CM increased cell growth, and treatment with 1α25(OH)2D3 or vitamin D3 pre-treated MSCs CM increased this further. Genomic microarray analysis of MDA-MD-231 and MCF7 breast cancer cells and of MSCs identified STAT3 and PDE4D as possible master mediators of the increased proliferation induced by CM from MCSs pre-treated with 1,25(OH)2D3. It also identified activation of signalling pathways STAT3, VDR/RXR, IL-6, IL-17, JAK/STAT3, CXCR4 for MDA-MB-231 and STAT3, NF-kB, ER/MAPK, HGF, IL-6 for MCF-7 cells. The effect of VDR knock down (KD) on breast and prostate cancer cell growth and tumour formation was studied in a mouse xenograft model. VDR knockdown in breast and prostate cancer cells decreased their tumour growth suggesting that the un-liganded VDR may have itself have proliferative actions which may present therapeutic a target in breast cancer and prostate cancer. The findings indicate that VDR, vitamin D and its metabolites can control cell growth during breast cancer by direct actions on cells, or indirectly by modulating the effects of MSCs on adjacent cancer cells.