The human estrogen receptor-alpha isoform hERalpha46 antagonizes the proliferative influence of hERalpha66 in MCF7 breast cancer cells.
The expression of two human estrogen receptor-alpha (hERalpha) isoforms has been characterized within estrogen receptor-alpha-positive breast cancer cell lines such as MCF7: the full-length hERalpha66 and the N terminally deleted hERalpha46, which is devoid of activation function (AF)-1. Although hERalpha66 is known to mediate the mitogenic effects that estrogens have on MCF7 cells, the exact function of hERalpha46 in these cells remains undefined. Here we show that, during MCF7 cell growth, hERalpha46 is mainly expressed in the nucleus at relatively low levels, whereas hERalpha66 accumulates in the nucleus. When cells reach confluence, the situation reverses, with hERalpha46 accumulating within the nucleus. Although hERalpha46 expression remains rather stable during an estrogen-induced cell cycle, its overexpression in proliferating MCF7 cells provokes a cell-cycle arrest in G(0)/G(1) phases. To gain further details on the influence of hERalpha46 on cell growth, we used PC12 estrogen receptor-alpha-negative cell line, in which stable transfection of hERalpha66 but not hERalpha46 allows estrogens to behave as mitogens. We next demonstrate that, in MCF7 cells, overexpression of hERalpha46 inhibits the hERalpha66-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, hERalpha46 antagonizes the proliferative action of hERalpha66 in MCF7 cells in part by inhibiting hERalpha66 AF-1 activity.
Penot
Graziella
G
Equipe d'Endocrinologie Moléculaire de la Reproduction, Unité Mixte de Recherche Centre National de la Recherche Scientifique 6026, Rennes, France.
Le Péron
Christine
C
Mérot
Yohann
Y
Grimaud-Fanouillère
Eva
E
Ferrière
François
F
Boujrad
Noureddine
N
Kah
Olivier
O
Saligaut
Christian
C
Ducouret
Bernadette
B
Métivier
Raphaël
R
Flouriot
Gilles
G
D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D019281:Dimerization; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004967:Estrogens; D005260:Female; D016193:G1 Phase; D005786:Gene Expression Regulation; D006801:Humans; D020218:Response Elements; D016192:Resting Phase, Cell Cycle; D014018:Tissue Distribution
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D004958:Estradiol