The nuclear receptors SF1 and LRH1 are expressed in endometrial cancer cells and regulate steroidogenic gene transcription by cooperating with AP-1 factors

Structure-based Discovery of Antagonists of Nuclear Receptor LRH-1

“…The established transcriptional targets of LRH-1 paired with ␤-catenin include CCND1 and CCNE1 genes as well as MYC genes known for controlling cell differentiation, growth, and proliferation (6,7,9). Because these developmental pathways and associated genes are re-activated during tumorigenesis (11)(12)(13)(14)(15)(16), an aberrant activity of LRH-1 is linked to different types of malignancies, including breast and endometrial cancers as well as intestinal tumors and cancer of the pancreas (17)(18)(19)(20)(21)(22)(23)(24). The LRH-1 recep-tor is also implicated in development of various metabolic disorders related to insufficient liver and pancreas functions (25)(26)(27).…”

LRH-1 May Rescue SF-1 Deficiency for Steroidogenesis: An in vitro<b> </b>and in vivo<b> </b>Study

“…Similar to our presented results, other investigators also found that SF-1-regulated genes are regulated by LRH-1. The effect of LRH-1 and SF-1 on steroid enzyme promoters CYP17A1 and HSD3B2 involved in androgen production was unambiguously stimulatory, although some differences in the strength of this effect were seen depending on the cell systems and experimental setup employed [Wang et al, 2001;Sirianni et al, 2002;Peng et al, 2003;Dubé et al, 2009;Yazawa et al, 2011]. We observed a weaker effect of LRH-1 on the CYP17A1 promoter but a similar effect on the HSD3B2 promoter when compared to SF-1 ( fig.…”

“…A second hit in another gene might explain the broad range of clinical manifestation. In our study, we therefore addressed the question whether the second hit is in the NR5A2 /LRH-1 gene because LRH-1 is a close family member of SF-1 and has known regulatory functions in steroidogenesis [Sirianni et al, 2002;Dubé et al, 2009;Yazawa et al, 2009]. In our cell model, we found that LRH-1 has similar transactivational activity on steroid enzyme promoters as SF-1, that it interacts with DAX-1 leading to a repression of transactivation, and that both LRH-1 and SF-1 wild-types are able to compensate for V20L SF-1, a previously shown severe loss of function NR5A1 mutation.…”

“…LRH-1 and SF-1 share target genes related to steroidogenesis and sex development such as STAR [Sirianni et al, 2002;Kim et al, 2004;Dubé et al, 2009], CYP11A1 [Kim et al, 2005], CYP17A1 [Wang et al, 2001;Sirianni et al, 2002;Yazawa et al, 2009], HSD3B2 [Peng et al, 2003;Dubé et al, 2009], CYP19A1 [Dubé et al, 2009], CYP11B1 [Sirianni et al, 2002], CYP11B2 [Sirianni et al, 2002], and WNT4 [Zhang et al, 2013]. In females, LRH-1 seems to play a major role in follicle maturation, ovulation and pregnancy [Duggavathi et al, 2008;Zhang et al, 2013], while its role in males is still poorly understood [Pezzi et al, 2004;Guo et al, 2007;Sierens et al, 2010].…”

“…A double hit in both genes would then cause the severe phenotype, while a heterozygote NR5A1 mutation alone would only cause a milder phenotype or even be compensated fully by the second gene when normal. We chose liver receptor homolog-1 (LRH-1, encoded by NR5A2 gene) for our 'second hit' candidate for the following reasons: (1) both transcription factors LRH-1 and SF-1 belong to the same NR5A family of transcription factors [Fayard et al, 2004], (2) they have a high sequence similarity [Fayard et al, 2004], (3) both bind to the same promoter-binding cis-elements [Wang et al, 2001;Kim et al, 2004;Dubé et al, 2009], (4) they share common target steroidogenic genes [Wang et al, 2001;Sirianni et al, 2002;Peng et al, 2003;Fayard et al, 2004;Kim et al, 2004Kim et al, , 2005Yazawa et al, 2009], and (5) both have a partially overlapping tissue expression pattern [Sirianni et al, 2002;Falender et al, 2003]. To date, no human mutations in NR5A2 have been described and, to our knowledge, no DSD patients have been analyzed for NR5A2 sequence variations.…”