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- Title
Unliganded estrogen receptor inhibits breast cancer cell growth through interaction with a cyclin-dependent kinase inhibitor (p21<sup>WAFI</sup>).
- Authors
Maynadier, Marie; Ramirez, Jean-Marie; Cathiard, Anne-Marie; Platet, Nadine; Gras, Delphine; Gleizes, Michel; Sheikh, M. Saeed; Nirde, Philippe; Garcia, Marcel
- Abstract
Estrogens are mitogenic in human breast cancer cells, but the presence of estrogen receptor α (ERα) is associated with a favorable prognosis in primary tumors and the molecular basis for this paradoxical relationship remains unknown. Here we show that ERα and ERα mutants devoid of ligand and DNA-binding domains inhibit cell growth in three-dimensional matrix as well as tumor formation in nude mice. Using in vitro and intracellular approaches, we have found that ERα, via its amino acids 184-283, interacts with cyclin-dependent kinase inhibitor p21WAF1. Both proteins exhibit mutual interactions in the absence of estrogens or in the presence of pure antiestrogen ICI182,780, whereas estradiol treatment disrupts their interactions. Cross-linking experiments reveal that these proteins are present in a larger complex of ~200 kDa that also contains cdk2 and cyclin E. We further demonstrate that the unliganded full-length ERα or the variant having the p21WAF1 interaction region significantly increases p21WAF1 expression, whereas ERα silencing reduces p21WAF1 levels and silencing of p21WAF1 is sufficient to prevent ERα-induced growth inhibition. Taken together, our results point to an antiproliferative function of the unliganded ERα through its physical interactions with p21WAF1 that may also explain the favorable prognosis of ERα-positive breast cancers.
- Subjects
ESTROGEN receptors; CANCER cells; BREAST cancer; CYCLIN-dependent kinases; ESTRADIOL; LABORATORY mice
- Publication
FASEB Journal, 2008, Vol 22, Issue 3, p671
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.07-9322com