title: Vitamin D growth inhibition of breast cancer cells: gene expression patterns assessed by cDNA microarray.
abstract: 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin D, is a potent inhibitor of breast cancer cell growth. Although it is evident that 1,25(OH)2D3 inhibits growth of both estrogen receptor alpha-positive [ER alpha(+)] and -negative [ER alpha(-)] breast cancer cells, the cellular pathways contributing to these effects remain unclear. We studied the gene expression patterns in ER alpha(+) MCF-7 and ER alpha(-) MDA MB 231 human breast cancer cells following 1,25(OH)2D3 treatment, using cDNA expression arrays. Both cell lines showed a significant induction of the 1,25(OH)2D3-dependent 24-hydroxylase gene, a marker for the actions of 1,25(OH)2D3. In MCF-7 cells, 51 genes were up-regulated and 19 genes were down-regulated. The up-regulated genes encoded cell adhesion molecules, growth factors/modulators, steroid receptors/co-activators, cytokines, kinases and transcription factors. Of the up-regulated genes, 40% were implicated in cell cycle regulation and apoptosis and included cyclin G1 and cyclin I, p21-activated kinase-1 (PAK-1), p53, retinoblastoma like-2 [Rb2 (p130)], insulin-like growth factor binding protein-5 (IGFBP5) and caspases. Among the down-regulated genes were ER alpha, growth factors, cytokines and several kinases. Some of these results were confirmed by real-time PCR. In MDA MB 231 cells, 20 genes were up-regulated and 13 genes were down-regulated. Very few genes directly implicated in cell cycle regulation were up-regulated. The matrix metalloproteinases formed a major class of genes that were down-regulated in the MDA MB 231 cells. Seven genes were commonly up-regulated in both cell lines and these included transforming growth factor (TGFbeta2) and Rb2 (p130). In conclusion, the gene expression profiles of the two cell lines studied were different with a few overlapping genes suggesting that different cellular pathways might be regulated by 1,25(OH)2D3 to exert its growth inhibitory effects in ER alpha(+) and ER alpha(-) cells.
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305-5103, USA.
authors.forename: Srilatha
authors.initials: S
authors.lastname: Swami
authors.forename: Nalini
authors.initials: N
authors.lastname: Raghavachari
authors.forename: Uwe R
authors.initials: UR
authors.lastname: Muller
authors.forename: Yijia P
authors.initials: YP
authors.lastname: Bao
authors.forename: David
authors.initials: D
authors.lastname: Feldman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D002117:Calcitriol / Q000494:pharmacology* / Q000627:therapeutic use; D004273:DNA, Neoplasm / Q000032:analysis; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D016133:Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D002117:Calcitriol