Cited by 280Ovarian cancer diagnosis and treatmentBRCA gene mutations in cancerCervical Cancer and HPV Research

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Modeling high-grade serous ovarian carcinogenesis from the fallopian tube

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Karst, Alison M., Levanon, Keren, Drapkin, Ronny·2011·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1017300108PMC PMC3088633

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Abstract

High-grade serous ovarian carcinoma (HGSOC) is a lethal disease for which improved screening and treatment strategies are urgently needed. Progress in these areas is impeded by our poor understanding of HGSOC pathogenesis. Most ovarian cancer research is based on the hypothesis that HGSOC arises from ovarian surface epithelial cells. However, recent studies suggest that >50% of high-grade serous carcinomas involving the ovary likely arise from fallopian tube epithelium. Therefore, limiting HGSOC research to modeling based on ovarian surface epithelium alone is inadequate. To address the need for a fallopian tube-based model of HGSOC, we have developed a system for studying human fallopian tube secretory epithelial cell (FTSEC) transformation. Our model is based on (i) immortalization of FTSECs isolated from primary samples of normal, nondiseased human fallopian tubes, (ii) transformation of FTSECs with defined genetic elements, and (iii) xenograft-based tumorigenic assays. We use our model to show that FTSECs immortalized with human telomerase reverse transcriptase (hTERT) plus SV40 large T and small T antigens are transformed by either oncogenic Ras (H-Ras(V12)) or c-Myc expression, leading to increased proliferation, clonogenicity, and anchorage-independent growth. Additionally, we demonstrate that FTSECs remain susceptible to c-Myc-mediated transformation in the absence of viral oncoproteins, by replacing SV40 large T and small T antigens with sh-p53, mutant CDK4 (CDK4(R24C)), and sh-PP2A-B56γ. Importantly, all transformed FTSECs gave rise to high-grade Müllerian carcinomas that were grossly, histologically, immunophenotypically, and genomically similar to human HGSOC. With this model, we will now be able to assess the transformative effects of specific genetic alterations on FTSECs in order to characterize their respective roles in HGSOC development.

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Authors: Karst, A. M., Levanon, K., & Drapkin, R.
Affiliations: Harvard University (US)
Brigham and Women's Hospital (US)
ORCID: Levanon, Keren
Drapkin, Ronny
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2011-04-18
Volume: 108
Issue: 18
Pages: 7547-7552
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1017300108
PMC: PMC3088633
OpenAlex: W2071014344
Cited by: 280
References: 37
Citations by year: 2026: 5 · 2025: 11 · 2024: 6 · 2023: 14 · 2022: 9 · 2021: 19 · 2020: 12 · 2019: 22 · 2018: 22 · 2017: 11 · 2016: 25 · 2015: 28 · 2014: 30 · 2013: 27 · 2012: 26
FWCI: 34.30
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Canadian Institutes of Health Research
National Cancer Institute (P50CA105009)
Topics: Health Sciences › Medicine › Oncology › Ovarian cancer diagnosis and treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
Health Sciences › Medicine › Epidemiology › Cervical Cancer and HPV Research
Keywords: high-grade serous ovarian cancer, fallopian tube epithelium, secretory epithelial cells, carcinogenesis, cell transformation, hTERT immortalization, oncogenic Ras, c-Myc, p53, CDK4, Müllerian carcinoma, xenograft tumorigenicity, ovarian surface epithelium
MeSH terms: Antigens, Polyomavirus Transforming, Carcinoma, Cell Transformation, Neoplastic, Epithelial Cells, Fallopian Tubes, Female, Humans, Immunohistochemistry, Microscopy, Fluorescence, Ovarian Neoplasms, Tumor Stem Cell Assay, Blotting, Western, Carcinogenicity Tests, Telomerase, Cell Line, Tumor, Comparative Genomic Hybridization

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Modeling high-grade serous ovarian carcinogenesis from the fallopian tube

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