PAPAS promotes differentiation of mammary epithelial cells and suppresses breast carcinogenesis
Summary: 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 differen...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-01-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723016558 |
| _version_ | 1797365561454231552 |
|---|---|
| author | Sijia Ren Feng Bai Viviane Schnell Clara Stanko Muriel Ritsch Tino Schenk Emanuel Barth Manja Marz Bin Wang Xin-Hai Pei Holger Bierhoff |
| author_facet | Sijia Ren Feng Bai Viviane Schnell Clara Stanko Muriel Ritsch Tino Schenk Emanuel Barth Manja Marz Bin Wang Xin-Hai Pei Holger Bierhoff |
| author_sort | Sijia Ren |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-03-08T16:50:45Z |
| format | Article |
| id | doaj.art-1c72a64a8d864b5791a60d74a4984cb5 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-08T16:50:45Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-1c72a64a8d864b5791a60d74a4984cb52024-01-05T04:24:40ZengElsevierCell Reports2211-12472024-01-01431113644PAPAS promotes differentiation of mammary epithelial cells and suppresses breast carcinogenesisSijia Ren0Feng Bai1Viviane Schnell2Clara Stanko3Muriel Ritsch4Tino Schenk5Emanuel Barth6Manja Marz7Bin Wang8Xin-Hai Pei9Holger Bierhoff10Institute 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, GermanyDepartment of Pathology, Shenzhen University Medical School, Shenzhen 518060, ChinaInstitute 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, GermanyDepartment 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, GermanyBioinformatics 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, GermanyDepartment 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, GermanyBioinformatics 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, GermanyBioinformatics 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, GermanyDepartment of General Surgery, Shenzhen Children’s Hospital, Shenzhen 518060, ChinaGuangdong 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; Corresponding authorInstitute 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; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723016558CP: Cancer |
| spellingShingle | Sijia Ren Feng Bai Viviane Schnell Clara Stanko Muriel Ritsch Tino Schenk Emanuel Barth Manja Marz Bin Wang Xin-Hai Pei Holger Bierhoff PAPAS promotes differentiation of mammary epithelial cells and suppresses breast carcinogenesis Cell Reports CP: Cancer |
| title | PAPAS promotes differentiation of mammary epithelial cells and suppresses breast carcinogenesis |
| title_full | PAPAS promotes differentiation of mammary epithelial cells and suppresses breast carcinogenesis |
| title_fullStr | PAPAS promotes differentiation of mammary epithelial cells and suppresses breast carcinogenesis |
| title_full_unstemmed | PAPAS promotes differentiation of mammary epithelial cells and suppresses breast carcinogenesis |
| title_short | PAPAS promotes differentiation of mammary epithelial cells and suppresses breast carcinogenesis |
| title_sort | papas promotes differentiation of mammary epithelial cells and suppresses breast carcinogenesis |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723016558 |
| work_keys_str_mv | AT sijiaren papaspromotesdifferentiationofmammaryepithelialcellsandsuppressesbreastcarcinogenesis AT fengbai papaspromotesdifferentiationofmammaryepithelialcellsandsuppressesbreastcarcinogenesis AT vivianeschnell papaspromotesdifferentiationofmammaryepithelialcellsandsuppressesbreastcarcinogenesis AT clarastanko papaspromotesdifferentiationofmammaryepithelialcellsandsuppressesbreastcarcinogenesis AT murielritsch papaspromotesdifferentiationofmammaryepithelialcellsandsuppressesbreastcarcinogenesis AT tinoschenk papaspromotesdifferentiationofmammaryepithelialcellsandsuppressesbreastcarcinogenesis AT emanuelbarth papaspromotesdifferentiationofmammaryepithelialcellsandsuppressesbreastcarcinogenesis AT manjamarz papaspromotesdifferentiationofmammaryepithelialcellsandsuppressesbreastcarcinogenesis AT binwang papaspromotesdifferentiationofmammaryepithelialcellsandsuppressesbreastcarcinogenesis AT xinhaipei papaspromotesdifferentiationofmammaryepithelialcellsandsuppressesbreastcarcinogenesis AT holgerbierhoff papaspromotesdifferentiationofmammaryepithelialcellsandsuppressesbreastcarcinogenesis |