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Unliganded estrogen receptor inhibits breast cancer cell growth through interaction with a cyclin-dependent kinase inhibitor (p21^WAF1)

Marie Maynadier^*,,1, Jean-Marie Ramirez^*,,1, Anne-Marie Cathiard^*,, Nadine Platet^*,, Delphine Gras^*,, Michel Gleizes, M. Saeed Sheikh, Philippe Nirde^*, and Marcel Garcia^*,,2

^* INSERM, Unité 826, Montpellier, France;

University of Montpellier 1, Montpellier, France; and

Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, USA

²Correspondence: INSERM Unité 826, CRLC, 208 rue des Apothicaires, 34298 Montpellier Cedex 1, France. E-mail: marcel.garcia{at}valdorel.fnclcc.fr

Estrogens are mitogenic in human breast cancer cells, but the presence of estrogen receptor (ER) is associated with a favorable prognosis in primary tumors and the molecular basis for this paradoxical relationship remains unknown. Here we show that ER and ER 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 ER, via its amino acids 184–283, interacts with cyclin-dependent kinase inhibitor p21^WAF1. Both proteins exhibit mutual interactions in the absence of estrogens or in the presence of pure antiestrogen ICI_182,780, 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 ER or the variant having the p21^WAF1 interaction region significantly increases p21^WAF1 expression, whereas ER silencing reduces p21^WAF1 levels and silencing of p21^WAF1 is sufficient to prevent ER-induced growth inhibition. Taken together, our results point to an antiproliferative function of the unliganded ER through its physical interactions with p21^WAF1 that may also explain the favorable prognosis of ER-positive breast cancers.—Maynadier, M., Ramirez, J.-M., Cathiard, A.-M., Platet, N., Gras, D., Gleizes, M., Sheikh, M. S., Nirde, P., Garcia, M. Unliganded estrogen receptor alpha inhibits breast cancer cell growth through interaction with a cyclin-dependent kinase inhibitor (p21^WAF1).

Key Words: cell cycle • steroid • proliferation