title: LRH-1 controls proliferation in breast tumor cells by regulating CDKN1A gene expression.
abstract: Liver receptor homolog-1 (LRH-1, NR5A2) is an orphan nuclear receptor that has an essential role in cancer progression, notably in breast cancer. Although its role in promoting cancer cell proliferation and migration is well documented, the molecular basis is not completely established. Here, we report that LRH-1 inhibition affects two- and three-dimensional cell proliferation of different types of breast cancer cells, including estrogen receptor α (ERα)-positive and triple-negative cells. This phenotype is accompanied by the upregulation of the cyclin-dependent kinase inhibitor CDKN1A (aka p21(CIP1/WAF1)) in a p53-independent manner. Chromatin immunoprecipitation analysis shows that LRH-1 cooperates with FOXA1 and binds directly to CDKN1A promoter and a distal regulatory region found at -62 kb from its transcriptional start sites, allowing repression of CDKN1A transcription. LRH-1 or FOXA1 depletion induces CDKN1A upregulation by removing histone deacetylase 2 from the promoter and distal regulatory elements and permitting histone acetylation in these regions. Analysis of breast cancer samples reveals that a high LRH-1 level is inversely correlated with CDKN1A expression in breast cancer patients and is associated with poor prognosis. This study reveals a novel mechanism of control of cell proliferation by LRH-1 regulating CDKN1A transcription in breast cancer cells, independent of ERα and p53 status. Targeting LRH-1 may provide an attractive prospect for treatment of tumors that are resistant to hormonal and targeted therapy.
authors.affiliation: Département de biologie, Faculté des sciences, Université de Sherbrooke, 2500 boulevard de l'Université, Sherbrooke, QC, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Bianco
authors.affiliation: Département de biologie, Faculté des sciences, Université de Sherbrooke, 2500 boulevard de l'Université, Sherbrooke, QC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Jangal
authors.affiliation: Département de biologie, Faculté des sciences, Université de Sherbrooke, 2500 boulevard de l'Université, Sherbrooke, QC, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Garneau
authors.affiliation: Département de biologie, Faculté des sciences, Université de Sherbrooke, 2500 boulevard de l'Université, Sherbrooke, QC, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Gévry
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000032:analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000502:physiology; D056464:Histone Deacetylase 2 / Q000502:physiology; D006801:Humans; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; C082631:NR5A2 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2