The nuclear receptor liver receptor homolog-1 is an estrogen receptor target gene.
Liver receptor homolog-1 (LRH-1) is a nuclear receptor previously known to have distinct functions during mouse development and essential roles in cholesterol homeostasis. Recently, a new role for LRH-1 has been discovered in tumor progression, giving LRH-1 potential transforming functions. In order to identify critical factors stimulating LRH-1 expression leading to deregulated cellular proliferation, we studied its expression and its regulation in several breast cancer cell lines. We observed that LRH-1 expression was increased in estrogen receptor (ER) alpha expressing cell lines, whereas weak-to-no expression was found in nonexpressing ERalpha cell lines. In MCF7, LRH-1 expression was highly induced after treatment with 17beta-estradiol (E2). This transcriptional regulation was the result of a direct binding of the ER to the LRH-1 promoter, as demonstrated by gelshift and chromatin immunoprecipitation assays. Interestingly, siRNA-mediated inactivation of LRH-1 decreased the E2-dependent proliferation of MCF7 cells. Finally, LRH-1 protein expression was detected by immunohistochemistry in tumor cells of human mammary ductal carcinomas. Altogether, these data demonstrate that LRH-1 is transcriptionally regulated by the ER alpha and reinforce the hypothesis that LRH-1 could exert potential oncogenic effects during breast cancer formation.
Annicotte
Jean-Sébastien
JS
Inserm Equipe Avenir, U540, 60 rue de Navacelles, Montpellier, France.
Chavey
Carine
C
Servant
Nadège
N
Teyssier
Jacques
J
Bardin
Aurélie
A
Licznar
Anne
A
Badia
Eric
E
Pujol
Pascal
P
Vignon
Françoise
F
Maudelonde
Thierry
T
Lazennec
Gwendal
G
Cavailles
Vincent
V
Fajas
Lluis
L
D001665:Binding Sites; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D047628:Estrogen Receptor alpha / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; C082631:NR5A2 protein, human; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors