The nuclear receptors SF1 and LRH1 are expressed in endometrial cancer cells and regulate steroidogenic gene transcription by cooperating with AP-1 factors.
Excessive exposure to estradiol represents the main risk factor for endometrial cancer. The abnormally high estradiol levels in the endometrium of women with endometrial cancer are most likely due to overproduction by the tumour itself. Endometrial cancer cells express the genes encoding the steroidogenic enzymes involved in estradiol synthesis. Here we used RT-PCR and Western blot to show that the nuclear receptors SF1 and LRH1, two well-known regulators of steroidogenic gene expression in gonadal and adrenal cells, are also expressed in endometrial cancer cell lines. By transient transfections, we found that SF1 and LRH1, but not the related nuclear receptor NUR77, can activate the promoters of three human steroidogenic genes: STAR, HSD3B2, and CYP19A1 PII. Similarly, forskolin but not PMA, could activate all three promoters. In addition, we found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. All together, our data provide novel insights into the mechanisms of steroidogenic gene expression in endometrial cancer cells and thus in the regulation of estradiol biosynthesis by tumour cells.
Dubé
Charlotte
C
Reproduction, Perinatal and Child Health, CHUQ Research Centre, CHUL Room T1-49, 2705 Laurier Blvd., Qué., Canada G1V 4G2.
Bergeron
Francis
F
Vaillant
Marie-Josée
MJ
Robert
Nicholas M
NM
Brousseau
Catherine
C
Tremblay
Jacques J
JJ
D001141:Aromatase / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D016889:Endometrial Neoplasms / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010750:Phosphoproteins / Q000378:metabolism; D011375:Progesterone Reductase / Q000378:metabolism; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism; D054339:Steroidogenic Factor 1 / Q000378:metabolism*; D013256:Steroids / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic; D000098682:Steroidogenic Acute Regulatory Protein
C539821:NR4A1 protein, human; C515057:NR5A1 protein, human; C082631:NR5A2 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D054339:Steroidogenic Factor 1; D013256:Steroids; D018808:Transcription Factor AP-1; D000098682:Steroidogenic Acute Regulatory Protein; D005576:Colforsin; C533068:3 beta-hydroxysteroid dehydrogenase type II; D011375:Progesterone Reductase; D001141:Aromatase