Prostaglandin E receptor EP1 suppresses breast cancer metastasis and is linked to survival differences and cancer disparities.
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.
Ma
Xinrong
X
University of Maryland, Greenebaum Cancer Center, Baltimore, MD 21201, USA.
Kundu
Namita
N
Ioffe
Olga B
OB
Goloubeva
Olga
O
Konger
Raymond
R
Baquet
Claudia
C
Gimotty
Phyllis
P
Reader
Jocelyn
J
Fulton
Amy M
AM
D000818:Animals; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011379:Prognosis; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*
D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; D058306:Receptors, Prostaglandin E, EP1 Subtype; D025521:Tumor Suppressor Proteins