title: Oestradiol reduces liver receptor homolog-1 mRNA transcript stability in breast cancer cell lines.
abstract: The expression of orphan nuclear receptor Liver Receptor Homolog-1 (LRH-1) is elevated in breast cancer and promotes proliferation, migration and invasion in vitro. LRH-1 expression is regulated by oestrogen (E2), with LRH-1 mRNA transcript levels higher in oestrogen receptor α (ERα) positive (ER+) breast cancer cells compared to ER- cells. However, the presence of LRH-1 protein in ER- cells suggests discordance between mRNA transcript levels and protein expression. To understand this, we investigated the impact of mRNA and protein stability in determining LRH-1 protein levels in breast cancer cells. LRH-1 transcript levels were significantly higher in ER+ versus ER- breast cancer cells lines; however LRH-1 protein was expressed at similar levels. We found LRH-1 mRNA and protein was more stable in ER- compared to ER+ cell lines. The tumor-specific LRH-1 variant isoform, LRH-1v4, which is highly responsive to E2, showed increased mRNA stability in ER- versus ER+ cells. In addition, in MCF-7 and T47-D cell lines, LRH-1 total mRNA stability was reduced with E2 treatment, this effect mediated by ERα. Our data demonstrates that in ER- cells, increased mRNA and protein stability contribute to the abundant protein expression levels. Expression and immunolocalisation of LRH-1 in ER- cells as well as ER- tumors suggests a possible role in the development of ER- tumors. The modulation of LRH-1 bioactivity may therefore be beneficial as a treatment option in both ER- and ER+ breast cancer.
authors.affiliation: Cancer Drug Discovery Laboratory, Prince Henry's Institute of Medical Research, Clayton, Victoria 3168, Australia.
authors.forename: Kyren A
authors.initials: KA
authors.lastname: Lazarus
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhao
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Knower
authors.forename: Sarah Q
authors.initials: SQ
authors.lastname: To
authors.forename: Ashwini L
authors.initials: AL
authors.lastname: Chand
authors.forename: Colin D
authors.initials: CD
authors.lastname: Clyne
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D006801:Humans; D020033:Protein Isoforms / Q000235:genetics; D055550:Protein Stability / Q000187:drug effects*; D020871:RNA Stability / Q000187:drug effects* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C082631:NR5A2 protein, human; D020033:Protein Isoforms; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D004958:Estradiol
keywords: ER; LRH-1; Liver Receptor Homolog-1; Oestrogen receptor alpha; mRNA stability; miRNA; micro RNA; oestrogen receptor