Cyclin E1 Deregulation Occurs Early in Secretory Cell Transformation to Promote Formation of Fallopian Tube-Derived High-Grade Serous Ovarian Cancers

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-02, Vol.74 (4), p.1141-1152
• Main Authors: KARST, Alison M, JONES, Paul M, VENA, Natalie, LIGON, Azra H, LIU, Joyce F, HIRSCH, Michelle S, ETEMADMOGHADAM, Dariush, BOWTELL, David D. L, DRAPKIN, Ronny
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cyclin E - genetics; Cyclin E - metabolism; Cystadenocarcinoma, Serous - genetics; Cystadenocarcinoma, Serous - metabolism; Cystadenocarcinoma, Serous - secondary; Epithelial Cells - pathology; Epithelial Cells - secretion; Fallopian Tube Neoplasms - genetics; Fallopian Tube Neoplasms - pathology; Fallopian Tubes - metabolism; Fallopian Tubes - pathology; Female; Female genital diseases; Gene Amplification - physiology; Gene Expression Regulation, Neoplastic; Gynecology. Andrology. Obstetrics; Humans; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - secondary; Pharmacology. Drug treatments; Tissue Array Analysis; Tumor Cells, Cultured; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-13-2247

The fallopian tube is now generally considered the dominant site of origin for high-grade serous ovarian carcinoma. However, the molecular pathogenesis of fallopian tube-derived serous carcinomas is poorly understood and there are few experimental studies examining the transformation of human fallopian tube cells. Prompted by recent genomic analyses that identified cyclin E1 (CCNE1) gene amplification as a candidate oncogenic driver in high-grade serous ovarian carcinoma, we evaluated the functional role of cyclin E1 in serous carcinogenesis. Cyclin E1 was expressed in early- and late-stage human tumor samples. In primary human fallopian tube secretory epithelial cells, cyclin E1 expression imparted malignant characteristics to untransformed cells if p53 was compromised, promoting an accumulation of DNA damage and altered transcription of DNA damage response genes related to DNA replication stress. Together, our findings corroborate the hypothesis that cyclin E1 dysregulation acts to drive malignant transformation in fallopian tube secretory cells that are the site of origin of high-grade serous ovarian carcinomas.