NOTCH3 OVEREXPRESSION AND CARBOPLATIN RESISTANCE IN OVARIAN CANCER

Am J Pathol. 2010 Jul 29. [Epub ahead of print]
Notch3 Overexpression Is Related to the Recurrence of Ovarian Cancer and Confers Resistance to Carboplatin.
Park JT, Chen X, Tropè CG, Davidson B, Shih IM, Wang TL.

From the Departments of Pathology,* Pathobiology Graduate Program, and Oncology, Gynecology, and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, Maryland; the Section for Gynecologic Oncology, Division of Gynecology and Obstetrics, and the Division of Pathology, Norwegian Radium Hospital, Oslo University Hospital; and The Medical Faculty, University of Oslo, Oslo, Norway.
Abstract

Amplification of the Notch3 locus has been detected in ovarian high-grade serous carcinoma (HGSC), the most common and malignant type of ovarian cancer. We have previously demonstrated that ovarian cancer cells, which amplified and overexpressed Notch3, were dependent on Notch3 signaling for cellular survival and growth. In this study, we provide new evidence that Notch3 expression is associated with recurrent postchemotherapy HGSCs. Moreover, patients with recurrent HGSCs in effusion with high Notch3 expression had a significantly worse clinical outcome, including reduced overall survival and shortened progression-free survival than did patients with low Notch3 expressing HGSC. Ectopic expression of the Notch3 intracellular domain led to an increase in IC50 for carboplatin in an ovarian surface epithelial cell line and in a low-grade serous carcinoma cell line that expressed undetectable levels of Notch3. Interestingly, expression of the Notch3 intracellular domain increased expression of several genes associated with embryonic stem cells including Nanog, Oct4, Klf4, Rex1, Rif1, Sall4, and NAC1 as well as an ATP-dependent transporter gene, ABCB1. Knockdown of Notch3 resulted in sensitization to carboplatin in OVCAR3 that expresses abundant Notch3. Taken together, the above findings suggest that Notch3 pathway activation reprograms tumor cells to assume an array of embryonic stem cell markers and participates in development of chemoresistance in HGSC.