Targets of 17β-oestradiol-indiuced apoptosis in colon cancer cells: A mechanism for the protective effects of hormone replacement therapy?

Abstract

Epidemiological studies show a strong link between postmenopausal hormone replacement therapy and decreased incidence of colorectal cancer. The colon cancer cell line, COLO 205, develops sensitivity to 17β-oestradiol (E2) in apoptosis assays with increasing passage number (>40), and we hypothesised that genes selectively regulated in multiply passaged cells were likely to be important in E2-related apoptosis. Gene array analysis was used to compare the patterns of genes up- or down-regulated in E2-sensitive and -insensitive cells. For some genes, changes in mRNA expression were confirmed by protein expression analyses. Changes found in response to E2 in multiply passaged cells, but not minimally passaged cells, included induction of growth arrest and DNA damage-inducible protein 153 (GADD153), and repression of Kirsten-Ras 2B (K-Ras-2B), metastasis inhibition factor NM23 and vascular endothelial growth factor. A second group of genes was regulated with E2 exposure in both cell types, and is unlikely to be critically involved in E2-associated apoptosis. These included up-regulation of butyrate response factor 1 (BRF1) and down-regulation of c-jun and the breast cancer associated ring domain gene known as BARD1. By comparing control arrays from the two cell populations, cAMP-response element-binding protein (CBP), which is associated with steroid receptor-dependent target gene transcription and the oncoprotein, tyrosine kinase-T3 (TPK-T3), were up-regulated whereas retinoic acid receptor α (RARα) was down-regulated in multiply passaged cells. This study provides evidence for selective regulation of genes in colon cancer cells by E2 indicates which of those regulated are likely to be involved in induced apoptosis, and suggests genes likely to be responsible for facilitation. © 2004 Society for Endocrinology.