title: Prostaglandin E receptor EP4 is a therapeutic target in breast cancer cells with stem-like properties.
abstract: The cyclooxygenase pathway is strongly implicated in breast cancer progression but the role of this pathway in the biology of breast cancer stem/progenitor cells has not been defined. Recent attention has focused on targeting the cyclooxygenase 2 (COX-2) pathway downstream of the COX-2 enzyme by blocking the activities of individual prostaglandin E (EP) receptors. Prostaglandin E receptor 4 (EP4) is widely expressed in primary invasive ductal carcinomas of the breast and antagonizing this receptor with small molecule inhibitors or shRNA directed to EP4 inhibits metastatic potential in both syngeneic and xenograft models. Breast cancer stem/progenitor cells are defined as a subpopulation of cells that drive tumor growth, metastasis, treatment resistance, and relapse. Mammosphere-forming breast cancer cells of human (MDA-MB-231, SKBR3) or murine (66.1, 410.4) origin of basal-type, Her-2 phenotype and/or with heightened metastatic capacity upregulate expression of both EP4 and COX-2 and are more tumorigenic compared to the bulk population. In contrast, luminal-type or non-metastatic counterparts (MCF7, 410, 67) do not increase COX-2 and EP4 expression in mammosphere culture. Treatment of mammosphere-forming cells with EP4 inhibitors (RQ-15986, AH23848, Frondoside A) or EP4 gene silencing, but not with a COX inhibitor (Indomethacin) reduces both mammosphere-forming capacity and the expression of phenotypic markers (CD44(hi)/CD24(low), aldehyde dehydrogenase) of breast cancer stem cells. Finally, an orally delivered EP4 antagonist (RQ-08) reduces the tumor-initiating capacity and markedly inhibits both the size of tumors arising from transplantation of mammosphere-forming cells and phenotypic markers of stem cells in vivo. These studies support the continued investigation of EP4 as a potential therapeutic target and provide new insight regarding the role of EP4 in supporting a breast cancer stem cell/tumor-initiating phenotype.
authors.affiliation: Department of Pathology, University of Maryland, Baltimore, MD, USA, nkundu@umaryland.edu.
authors.forename: Namita
authors.initials: N
authors.lastname: Kundu
authors.forename: Xinrong
authors.initials: X
authors.lastname: Ma
authors.forename: Tyler
authors.initials: T
authors.lastname: Kochel
authors.forename: Olga
authors.initials: O
authors.lastname: Goloubeva
authors.forename: Paul
authors.initials: P
authors.lastname: Staats
authors.forename: Keyata
authors.initials: K
authors.lastname: Thompson
authors.forename: Stuart
authors.initials: S
authors.lastname: Martin
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Reader
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Take
authors.forename: Peter
authors.initials: P
authors.lastname: Collin
authors.forename: Amy
authors.initials: A
authors.lastname: Fulton
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D007150:Immunohistochemistry; D016130:Immunophenotyping; D051379:Mice; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured
chemical_list: D058309:Receptors, Prostaglandin E, EP4 Subtype; D051546:Cyclooxygenase 2