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Resf1 is a compound G4 quadruplex-associated tumor suppressor for triple negative breast cancer.
Majocha, Megan R; Jackson, Devin E; Ha, Ngoc-Han; Amin, Ruhul; Pangrácová, Marie; Ross, Christina R; Yang, Howard H; Lee, Maxwell P; Hunter, Kent W.
Afiliação
  • Majocha MR; Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
  • Jackson DE; Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, United States of America.
  • Ha NH; Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
  • Amin R; Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, United States of America.
  • Pangrácová M; Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
  • Ross CR; Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
  • Yang HH; Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
  • Lee MP; Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
  • Hunter KW; Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS Genet ; 20(5): e1011236, 2024 May.
Article em En | MEDLINE | ID: mdl-38722825
ABSTRACT
Patients with ER-negative breast cancer have the worst prognosis of all breast cancer subtypes, often experiencing rapid recurrence or progression to metastatic disease shortly after diagnosis. Given that metastasis is the primary cause of mortality in most solid tumors, understanding metastatic biology is crucial for effective intervention. Using a mouse systems genetics approach, we previously identified 12 genes associated with metastatic susceptibility. Here, we extend those studies to identify Resf1, a poorly characterized gene, as a novel metastasis susceptibility gene in ER- breast cancer. Resf1 is a large, unstructured protein with an evolutionarily conserved intron-exon structure, but with poor amino acid conservation. CRISPR or gene trap mouse models crossed to the Polyoma Middle-T antigen genetically engineered mouse model (MMTV-PyMT) demonstrated that reduction of Resf1 resulted in a significant increase in tumor growth, a shortened overall survival time, and increased incidence and number of lung metastases, consistent with patient data. Furthermore, an analysis of matched tail and primary tissues revealed loss of the wildtype copy in tumor tissue, consistent with Resf1 being a tumor suppressor. Mechanistic analysis revealed a potential role of Resf1 in transcriptional control through association with compound G4 quadruplexes in expressed sequences, particularly those associated with ribosomal biogenesis. These results suggest that loss of Resf1 enhances tumor progression in ER- breast cancer through multiple alterations in both transcriptional and translational control.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Repressoras / Neoplasias de Mama Triplo Negativas Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Repressoras / Neoplasias de Mama Triplo Negativas Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article