Differential gene expression of sulindac-treated human breast epithelial cells.

ABSTRACT

Breast cancer is the most common malignancy and the second major cause of cancer-related deaths among women in the United States. Recent advances in the molecular genetics of breast cancer have identified various genes associated with tumorigenesis. There is evidence that non-steroidal anti-inflammatory drugs, e.g. sulindac, have some anti-proliferative effects on various tumors involving altered p53 function. Most of these studies have been performed with various human colon carcinoma cell lines and few of them focus on non-malignant proliferative human mammary epithelial cell lines. Therefore, the present study was undertaken to analyze the differentially expressed genes of the p53 signaling pathway by means of a gene array for the immortalized human breast epithelial cell line, MCF-10F, treated with sulindac. Out of the total 96 genes, only 17 were altered by the drug treatment. Among these 17 genes, 6 showed significant alteration (Q > 2.0), whereas 11 genes showed moderate alterations. Altered genes included BRCA1 associated protein-1 [ubiquitin carboxy-terminal hydrolase (bap1)]; cell division cycle 2, G1 to S and G2 to M [cdk1(cdc2)]; and DNA-damage-inducible transcript 1 (gadd45), which were down-regulated. However, N-myc gene 1 (rtp), promyelocytic leukemia (pml), and nuclear factor of kappa-light polypeptide gene enhancer in B-cell 3 and p65 [avian (rel A)] were up-regulated. Northern blot analysis confirmed some of these alterations. The alteration of p53 signaling pathway gene markers by sulindac treatment can give us valuable information about the response to drug treatments in a proliferative cell population.