TY - JOUR
T1 - Notch3 overexpression is related to the recurrence of ovarian cancer and confers resistance to carboplatin
AU - Park, Joon Tae
AU - Chen, Xu
AU - Tropè, Claes G.
AU - Davidson, Ben
AU - Shih, Ie Ming
AU - Wang, Tian Li
N1 - Funding Information:
Supported by the American Cancer Society (grant RSG-08−174−01-GMC to T.-L.W. ), the Ovarian Cancer Research Fund (T.-L.W.), a National Institutes of Health (NIH) Specialized Program of Research Excellence (SPORE) Career Development Award (T.-L.W.), NIH National Cancer Institute (grants R01-CA103937 to I.-M.S. and R01-CA129080 to I.M.S. ), and the Inger and Jon Fredriksen Foundation for Ovarian Cancer Research (B.D.).
PY - 2010/9
Y1 - 2010/9
N2 - 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 carbo-platin 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.
AB - 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 carbo-platin 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.
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U2 - 10.2353/ajpath.2010.100316
DO - 10.2353/ajpath.2010.100316
M3 - Article
C2 - 20671266
AN - SCOPUS:77956522571
SN - 0002-9440
VL - 177
SP - 1087
EP - 1094
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 3
ER -