Prostaglandin E Receptor EP1 Suppresses Breast Cancer Metastasis and Is Linked to Survival Differences and Cancer Disparities

被引:36
作者
Ma, Xinrong
Kundu, Namita [2 ]
Ioffe, Olga B. [2 ]
Goloubeva, Olga [2 ]
Konger, Raymond [4 ]
Baquet, Claudia [2 ]
Gimotty, Phyllis [5 ]
Reader, Jocelyn
Fulton, Amy M. [1 ,2 ,3 ]
机构
[1] Univ Maryland, Greenebaum Canc Ctr, Sch Med, Baltimore, MD 21201 USA
[2] Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA
[3] Baltimore Vet Adm Med Ctr, Baltimore, MD USA
[4] Indiana Univ, Sch Med, Indianapolis, IN USA
[5] Univ Penn, Sch Med, Philadelphia, PA 19104 USA
关键词
PROTEIN-COUPLED RECEPTORS; PROSTANOID RECEPTORS; COLON CARCINOGENESIS; TUMOR-DEVELOPMENT; E-2; RECEPTORS; MAMMARY-TUMOR; KNOCKOUT MICE; SUBTYPE EP4; EXPRESSION; CELLS;
D O I
10.1158/1541-7786.MCR-10-0003
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Cyclooxygenase-2 is frequently overexpressed and associated with poor prognosis in breast cancer. The cyclooxygenase-2 product prostaglandin E-2 elicits cellular responses through four G-protein-coupled receptors, designated EP1 to EP4, coupled to distinct intracellular signaling pathways. EP4, expressed on malignant breast cells, promotes metastasis; however, a role for EP1 in metastasis has not been investigated. Using a murine model of metastatic breast cancer, we now show that pharmacologic antagonism of EP1 with SC19220 or AH6809 promoted lung colonization of mammary tumor cells by 3.7- to 5.4-fold. Likewise, reducing EP1 gene expression by shRNA also increased metastatic capacity relative to cells transfected with nonsilencing vector but did not affect the size of transplanted tumors. Examination of invasive ductal carcinomas by immunohistochemistry shows that EP1 was detected in both the cytoplasm and nucleus of benign ducts as well as malignant cells in some samples, but was absent or limited to either the nucleus or cytoplasm in other malignant samples. Overall survival for women with tumors that were negative for nuclear EP1 was significantly worse than for women with EP1 expression (P=0.008). There was no difference in survival for women with differences in cytoplasmic EP1 expression (P=0.46). Comparing EP1 mRNA in breast tumors from African American and European American women revealed that many more African American breast tumors lacked detectable EP1 mRNA (P=0.04). These studies support the hypothesis that EP1 functions as a metastasis suppressor and that loss of nuclear EP1 is associated with poorer overall survival and may contribute to disparities in outcome in different populations. Mol Cancer Res; 8(10); 1310-8. (C) 2010 AACR.
引用
收藏
页码:1310 / 1318
页数:9
相关论文
共 38 条
[1]   Nuclear localization of prostaglandin E2 receptors [J].
Bhattacharya, M ;
Peri, KG ;
Almazan, G ;
Ribeiro-Da-Silva, A ;
Shichi, H ;
Durocher, Y ;
Abramovitz, M ;
Hou, X ;
Varma, DR ;
Chemtob, S .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (26) :15792-15797
[2]   Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor [J].
Buchanan, FG ;
Wang, DZ ;
Bargiacchi, F ;
DuBois, RN .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (37) :35451-35457
[3]   Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression [J].
Chang, SH ;
Liu, CH ;
Conway, R ;
Han, DK ;
Nithipatikom, K ;
Trifan, OC ;
Lane, TF ;
Hla, T .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (02) :591-596
[4]   GPCR antagonists as an alternative to COX-2 inhibitors:: a case for the PGE2 EP1 receptor [J].
Dore, Sylvain .
TRENDS IN PHARMACOLOGICAL SCIENCES, 2006, 27 (09) :458-460
[5]   Prostanoid receptors and phosphatidylinositol 3-kinase: a pathway to cancer? [J].
Fujino, H ;
Regan, JW .
TRENDS IN PHARMACOLOGICAL SCIENCES, 2003, 24 (07) :335-340
[6]  
FULTON AM, 1991, CANCER RES, V51, P2047
[7]   Targeting prostaglandin E EP receptors to inhibit metastasis [J].
Fulton, Amy M. ;
Ma, Xinrong ;
Kundu, Namita .
CANCER RESEARCH, 2006, 66 (20) :9794-9797
[8]   G-protein-coupled receptors signalling at the cell nucleus: an emerging paradigm [J].
Gobeil, Fernand, Jr. ;
Fortier, Audrey ;
Zhu, Tang ;
Bossolasco, Michela ;
Leduc, Martin ;
Grandbois, Michel ;
Heveker, Nikolaus ;
Bkaily, Ghassan ;
Chemtob, Sylvain ;
Barbaz, David .
CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY, 2006, 84 (3-4) :287-297
[9]   RETRACTED: Modulation of Stat3 activation by the cytosolic phospholipase A2α and cyclooxygenase-2-controlled prostaglandin E2 signaling pathway (Retracted Article) [J].
Han, Chang ;
Demetris, A. Jake ;
Stolz, Donna B. ;
Xu, Lihong ;
Lim, Kyu ;
Wu, Tong .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (34) :24831-24846
[10]   Prostaglandin E2 regulates tumor angiogenesis in prostate cancer [J].
Jain, Shalini ;
Chakraborty, Goutam ;
Raja, Remya ;
Kale, Smita ;
Kundu, Gopal C. .
CANCER RESEARCH, 2008, 68 (19) :7750-7759