Citation of original article:
S. Mukherjee, S. E. Conrad. Journal of Biological Chemistry 2005; 280: 17616–17625.
Abstract of the original article:
Oestrogen rapidly induces expression of the proto-oncogene c-Myc. c-Myc is required for oestrogen-stimulated proliferation of breast cancer cells, and deregulated c-Myc expression has been implicated in antioestrogen resistance. In this report, we investigate the mechanism(s) by which c-Myc mediates oestrogen-stimulated proliferation and contributes to cell cycle progression in the presence of antioestrogen. The MCF-7 cell line is a model of oestrogen-dependent, antioestrogen-sensitive human breast cancer. Using stable MCF-7 derivatives with inducible c-Myc expression, we demonstrated that in antioestrogen-treated cells, the elevated mRNA and protein levels of p21WAF1/CIP1, a cell cycle inhibitor, decreased upon either c-Myc induction or oestrogen treatment. Expression of p21 blocked c-Myc-mediated cell cycle progression in the presence of antioestrogen, suggesting that the decrease in p21WAF1/CIP1 is necessary for this process. Using RNA interference to suppress c-Myc expression, we further established that c-Myc is required for oestrogen-mediated decreases in p21WAF1/CIP1. Finally, we observed that neither c-Myc nor p21WAF1/CIP1 is regulated by oestrogen or antioestrogen in an antioestrogen-resistant MCF-7 derivative. The p21 levels in the antioestrogen-resistant cells increased when c-Myc expression was suppressed, suggesting that loss of p21 regulation was a consequence of constitutive c-Myc expression. Together, these studies implicate p21WAF1/CIP1 as an important target of c-Myc in breast cancer cells and provide a link between oestrogen, c-Myc, and the cell cycle machinery. They further suggest that aberrant c-Myc expression, which is frequently observed in human breast cancers, can contribute to antioestrogen resistance by altering p21WAF1/CIP1 regulation.