Date of Graduation
Previous studies demonstrated that acetaminophen-induced proliferation of estrogen (E2)-responsive breast cancer cells via an estrogen receptor (ER)-dependent pathway (Harnagea-Theophilus et al., 1999). Studies reported here tested the hypothesis that acetaminophen stimulates proliferation of E2-responsive breast cancer cells by activating ER as a transcription factor and inducing expression of E2-regulated genes. ER binding assays demonstrated that acetaminophen does not compete with E2 for ER binding in MCF-7 cells, indicating that acetaminophen does not bind ER in a manner similar to E2. Ribonuclease protection assays compared the effects of acetaminophen and E2 on expression of selected genes (c-myc, c-fos, cyclin D1, bcl-2, bax, gadd45, mcl-1, p53, p21CIP1/WAF1 and bcl-xL) in E2-responsive (MCF-7) and E2-nonresponsive (MDA-MB-231) breast cancer cells. Acetaminophen and E2 increased c-myc RNA levels in MCF-7 cells, consistent with a mitogenic activity of these compounds in MCF-7 cells. However, the magnitude and time course of acetaminophen and E2 induction of c-myc differed. Furthermore, the expression patterns of the other E2-sensitive genes differed dramatically in response to acetaminophen and to E2, indicating that acetaminophen does not activate ER as a transcription factor in the same manner as E2. Additionally, gel shift assays demonstrated that acetaminophen, but not E2, induced NF-kB activity âˆ¼40% in MCF-7 cells, whereas E2, but not acetaminophen, induced AP-1 activity âˆ¼50% in MCF-7 cells. These studies demonstrate that acetaminophen and E2 act via different pathways in E2-responsive breast cancer cells and suggest that acetaminophen may stimulate proliferation and c-myc RNA expression in MCF-7 cells via increased NF-kB activity. In contrast to MCF-7 cells, acetaminophen and E2 appear to have opposing effects on the expression of some E2-regulated genes in endometrial adenocarcinoma (Ishikawa) cells.
Gadd, Samantha Lynn, "Acetaminophen-induced proliferation of estrogen -responsive breast cancer cells is associated with increased c-myc RNA expression and NF-kB activity." (2001). Graduate Theses, Dissertations, and Problem Reports. 8883.