Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca;Tp53;Pten models

Ruth Perets; Gregory A Wyant; Katherine W Muto; Jonathan G Bijron; Barish B Poole; Kenneth T Chin; Jin Yun H Chen; Anders W Ohman; Corey D Stepule; Soongu Kwak; Alison M Karst; Michelle S Hirsch; Sunita R Setlur; Christopher P Crum; Daniela M Dinulescu; Ronny Drapkin

doi:10.1016/j.ccr.2013.10.013

Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca;Tp53;Pten models

Cancer Cell. 2013 Dec 9;24(6):751-65. doi: 10.1016/j.ccr.2013.10.013.

Authors

Ruth Perets¹, Gregory A Wyant², Katherine W Muto², Jonathan G Bijron³, Barish B Poole², Kenneth T Chin², Jin Yun H Chen², Anders W Ohman², Corey D Stepule², Soongu Kwak¹, Alison M Karst¹, Michelle S Hirsch³, Sunita R Setlur², Christopher P Crum³, Daniela M Dinulescu⁴, Ronny Drapkin⁵

Affiliations

¹ Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
² Eugene Braunwald Research Center, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
³ Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁴ Eugene Braunwald Research Center, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA; Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: ddinulescu@rics.bwh.harvard.edu.
⁵ Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: ronny_drapkin@dfci.harvard.edu.

Abstract

High-grade serous ovarian carcinoma presents significant clinical and therapeutic challenges. Although the traditional model of carcinogenesis has focused on the ovary as a tumor initiation site, recent studies suggest that there may be additional sites of origin outside the ovary, namely the secretory cells of the fallopian tube. Our study demonstrates that high-grade serous tumors can originate in fallopian tubal secretory epithelial cells and also establishes serous tubal intraepithelial carcinoma as the precursor lesion to high-grade serous ovarian and peritoneal carcinomas in animal models targeting the Brca, Tp53, and Pten genes. These findings offer an avenue to address clinically important questions that are critical for cancer prevention and early detection in women carrying BRCA1 and BRCA2 mutations.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Transformation, Neoplastic*
Cystadenocarcinoma, Serous / etiology*
Cystadenocarcinoma, Serous / genetics
Cystadenocarcinoma, Serous / pathology
Epithelium / pathology
Fallopian Tube Neoplasms / pathology*
Female
Genes, BRCA1*
Genes, BRCA2*
Genes, p53
Integrases / genetics
Mice
Mice, Inbred C57BL
Neoplasm Grading
Ovarian Neoplasms / etiology*
Ovarian Neoplasms / genetics
Ovarian Neoplasms / pathology
PAX8 Transcription Factor
PTEN Phosphohydrolase / genetics
Paired Box Transcription Factors / genetics
Paired Box Transcription Factors / physiology
Precancerous Conditions / pathology*

Substances

PAX8 Transcription Factor
Paired Box Transcription Factors
Pax8 protein, mouse
Cre recombinase
Integrases
PTEN Phosphohydrolase
Pten protein, mouse

Associated data

GEO/GSE49827

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding