Abstract
Estrogen rapidly induces expression of the proto-oncogene c-myc. c-Myc is required for estrogen-stimulated proliferation of breast cancer cells, and deregulated c-Myc expression has been implicated in antiestrogen resistance. In this report, we investigate the mechanism(s) by which c-Myc mediates estrogen-stimulated proliferation and contributes to cell cycle progression in the presence of antiestrogen. The MCF-7 cell line is a model of estrogen-dependent, antiestrogen-sensitive human breast cancer. Using stable MCF-7 derivatives with inducible c-Myc expression, we demonstrated that in antiestrogen-treated cells, the elevated mRNA and protein levels of p21(WAF1/CIP1), a cell cycle inhibitor, decreased upon either c-Myc induction or estrogen treatment. Expression of p21 blocked c-Myc-mediated cell cycle progression in the presence of antiestrogen, suggesting that the decrease in p21 is necessary for this process. Using RNA interference to suppress c-Myc expression, we further established that c-Myc is required for estrogen-mediated decreases in p21(WAF1/CIP1). Finally, we observed that neither c-Myc nor p21(WAF1/CIP1) is regulated by estrogen or antiestrogen in an antiestrogen-resistant MCF-7 derivative. The p21 levels in the antiestrogen-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 p21(WAF1/CIP1) as an important target of c-Myc in breast cancer cells and provide a link between estrogen, 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 antiestrogen resistance by altering p21(WAF1/CIP1) regulation.
Highlights
A majority of estrogen receptor (ER)1-positive breast tumors require estrogenic steroids such as 17-estradiol (E2) for proliferation and can be treated with antiestrogens that antago
A previous study demonstrated that decreasing p21 levels with antisense oligonucleotides is sufficient to cause cell cycle progression of ICI-treated cells [22]. Based on this finding and our current results, we propose that a key mechanism by which c-Myc promotes proliferation of breast cancer cells in the presence of ICI is by decreasing p21 levels
Various mechanisms have been proposed to account for acquired antiestrogen resistance in breast cancer cells, but since E2 and antiestrogens control cell cycle progression [56, 57], the development of resistance must be associated with changes in cell cycle regulation
Summary
A majority of estrogen receptor (ER)1-positive breast tumors require estrogenic steroids such as 17-estradiol (E2) for proliferation and can be treated with antiestrogens that antago-. Using stable MCF-7 derivatives with inducible c-Myc expression, we demonstrated that in antiestrogen-treated cells, the elevated mRNA and protein levels of p21WAF1/CIP1, a cell cycle inhibitor, decreased upon either c-Myc induction or estrogen treatment.
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