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The Human Estrogen Receptor- Isoform hER46 Antagonizes the Proliferative Influence of hER66 in MCF7 Breast Cancer Cells

Equipe d’Endocrinologie Moléculaire de la Reproduction, Unité Mixte de Recherche Centre National de la Recherche Scientifique 6026, 35042 Rennes Cedex, France

Address all correspondence and requests for reprints to: Gilles Flouriot, Equipe d’Endocrinologie Moléculaire de la Reproduction, Unité Mixte de Recherche Centre National de la Recherche Scientifique 6026, Université de Rennes I, 35042 Rennes Cedex, France. E-mail: gilles.flouriot{at}univ-rennes1.fr.

The expression of two human estrogen receptor- (hER) isoforms has been characterized within estrogen receptor--positive breast cancer cell lines such as MCF7: the full-length hER66 and the N terminally deleted hER46, which is devoid of activation function (AF)-1. Although hER66 is known to mediate the mitogenic effects that estrogens have on MCF7 cells, the exact function of hER46 in these cells remains undefined. Here we show that, during MCF7 cell growth, hER46 is mainly expressed in the nucleus at relatively low levels, whereas hER66 accumulates in the nucleus. When cells reach confluence, the situation reverses, with hER46 accumulating within the nucleus. Although hER46 expression remains rather stable during an estrogen-induced cell cycle, its overexpression in proliferating MCF7 cells provokes a cell-cycle arrest in G₀/G₁ phases. To gain further details on the influence of hER46 on cell growth, we used PC12 estrogen receptor--negative cell line, in which stable transfection of hER66 but not hER46 allows estrogens to behave as mitogens. We next demonstrate that, in MCF7 cells, overexpression of hER46 inhibits the hER66-mediated estrogenic induction of all AF-1-sensitive reporters: c-fos and cyclin D1 as well as estrogen-responsive element-driven reporters. Our data indicate that this inhibition occurs likely through functional competitions between both isoforms. In summary, hER46 antagonizes the proliferative action of hER66 in MCF7 cells in part by inhibiting hER66 AF-1 activity.

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