PAPAS promotes differentiation of mammary epithelial cells and suppresses breast carcinogenesis.

CP: Cancer R-loops breast cancer epigenetics lactogenic differentiation long non-coding RNA mammary epithelium rRNA genes

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
04 Jan 2024
Historique:
received: 31 03 2023
revised: 18 10 2023
accepted: 19 12 2023
medline: 5 1 2024
pubmed: 5 1 2024
entrez: 5 1 2024
Statut: aheadofprint

Résumé

Extensive remodeling of the female mammary epithelium during development and pregnancy has been linked to cancer susceptibility. The faithful response of mammary epithelial cells (MECs) to hormone signaling is key to avoiding breast cancer development. Here, we show that lactogenic differentiation of murine MECs requires silencing of genes encoding ribosomal RNA (rRNA) by the antisense transcript PAPAS. Accordingly, knockdown of PAPAS derepresses rRNA genes, attenuates the response to lactogenic hormones, and induces malignant transformation. Restoring PAPAS levels in breast cancer cells reduces tumorigenicity and lung invasion and activates many interferon-regulated genes previously linked to metastasis suppression. Mechanistically, PAPAS transcription depends on R-loop formation at the 3' end of rRNA genes, which is repressed by RNase H1 and replication protein A (RPA) overexpression in breast cancer cells. Depletion of PAPAS and upregulation of RNase H1 and RPA in human breast cancer underpin the clinical relevance of our findings.

Identifiants

DOI: 10.1016/j.celrep.2023.113644 PMID: 38180837
pubmed: 38180837
pii: S2211-1247(23)01655-8
doi: 10.1016/j.celrep.2023.113644
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

113644

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

Auteurs

Sijia Ren (S)

Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine (CMB), Friedrich Schiller University Jena, Hans-Knöll-Str. 2, 07745 Jena, Germany; Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Anatomy and Histology, Shenzhen University Medical School, Shenzhen 518060, China; Leibniz-Institute on Aging-Fritz Lipmann Institute (FLI), Beutenbergstr. 11, 07745 Jena, Germany.

Feng Bai (F)

Department of Pathology, Shenzhen University Medical School, Shenzhen 518060, China.

Viviane Schnell (V)

Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine (CMB), Friedrich Schiller University Jena, Hans-Knöll-Str. 2, 07745 Jena, Germany; Leibniz-Institute on Aging-Fritz Lipmann Institute (FLI), Beutenbergstr. 11, 07745 Jena, Germany.

Clara Stanko (C)

Department of Hematology and Medical Oncology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Jena, Hans-Knöll-Str. 2, 07745 Jena, Germany.

Muriel Ritsch (M)

Bioinformatics Core Facility Jena, Friedrich Schiller University Jena, Leutragraben 1, 07743 Jena, Germany; RNA Bioinformatics/High Throughput Analysis, Faculty of Mathematics and Computer Science, Leutragraben 1, 07743 Jena, Germany.

Tino Schenk (T)

Department of Hematology and Medical Oncology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Jena, Hans-Knöll-Str. 2, 07745 Jena, Germany.

Emanuel Barth (E)

Bioinformatics Core Facility Jena, Friedrich Schiller University Jena, Leutragraben 1, 07743 Jena, Germany; RNA Bioinformatics/High Throughput Analysis, Faculty of Mathematics and Computer Science, Leutragraben 1, 07743 Jena, Germany.

Manja Marz (M)

Bioinformatics Core Facility Jena, Friedrich Schiller University Jena, Leutragraben 1, 07743 Jena, Germany; RNA Bioinformatics/High Throughput Analysis, Faculty of Mathematics and Computer Science, Leutragraben 1, 07743 Jena, Germany.

Bin Wang (B)

Department of General Surgery, Shenzhen Children's Hospital, Shenzhen 518060, China.

Xin-Hai Pei (XH)

Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Anatomy and Histology, Shenzhen University Medical School, Shenzhen 518060, China. Electronic address: peixinhai@szu.edu.cn.

Holger Bierhoff (H)

Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine (CMB), Friedrich Schiller University Jena, Hans-Knöll-Str. 2, 07745 Jena, Germany; Leibniz-Institute on Aging-Fritz Lipmann Institute (FLI), Beutenbergstr. 11, 07745 Jena, Germany. Electronic address: holger.bierhoff@uni-jena.de.

Classifications MeSH