Identification and Pharmacological Targeting of Treatment-Resistant, Stem-like Breast Cancer Cells for Combination Therapy.

Tumors frequently harbor isogenic yet epigenetically distinct subpopulations of multi-potent cells with high tumor-initiating potential-often called Cancer Stem-Like Cells (CSLCs). These can display preferential resistance to standard-of-care chemotherapy. Single-cell analyses can help elucidate Master Regulator (MR) proteins responsible for governing the transcriptional state of these cells, thus revealing complementary dependencies that may be leveraged via combination therapy.

The number of vitamin D receptor binding sites defines the different vitamin D responsiveness of the CYP24 gene in malignant and normal mammary cells.

Primary 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3))-responding genes are controlled by the vitamin D receptor (VDR) binding to specific sites (VDREs) that are located within the regulatory regions of these genes. According to previous studies, the gene encoding 25-dihydroxyvitamin D(3) 24-hydroxylase, CYP24, which is the strongest known 1alpha,25(OH)(2)D(3)-responsive gene, has multiple VDREs that locate within the proximal and the distal promoter. However, it has remained unclear, what is the biological role of these regions and how they participate in the regulation of transcription.

Selective use of multiple vitamin D response elements underlies the 1 alpha,25-dihydroxyvitamin D3-mediated negative regulation of the human CYP27B1 gene.

The human 25-hydroxyvitamin D3 (25(OH)D3) 1alpha-hydroxylase, which is encoded by the CYP27B1 gene, catalyzes the metabolic activation of the 25(OH)D3 into 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3), the most biologically potent vitamin D3 metabolite. The most important regulator of CYP27B1 gene activity is 1alpha,25(OH)2D3 itself, which down-regulates the gene. The down-regulation of the CYP27B1 gene has been proposed to involve a negative vitamin D response element (nVDRE) that is located approximately 500 bp upstream from transcription start site (TSS).