Abstract
Abstract There is an urgent need to identify mechanisms underlying the survival of cells expressing cancer stem cell or tumor-initiating properties. The cyclooxygenase-2 (COX-2) pathway is highly expressed in many breast tumors and contributes to poor outcomes. The COX-2 product prostaglandin E2 (PGE2) promotes tumor growth and metastasis by acting on the G-protein-coupled receptor EP4. We compared the expression and function of COX-2 and EP4 in mammosphere-forming and bulk populations derived from a panel of human and murine luminal and basal type tumor cells with different metastatic capacities. Expression of both EP4 and COX-2 were markedly increased in mammosphere-forming cells derived from basal and/or metastatic cells relative to the bulk population, but neither COX-2 or EP4 levels were elevated in mammospheres derived from luminal or non-metastatic cells. Breast cancer stem cells, expressing elevated EP4 are correspondingly more sensitive to inhibition with EP4 antagonists both in vitro and in limiting-dilution assays in vivo. Somewhat to our surprise, cancer stem cells remain relatively sensitive to lysis by Natural Killer cells. We have also shown that EP4 blockade protects NK cells from tumor-induced immune suppression. These studies identify EP4 as a potential therapeutic target in the general tumor cell population and show that EP4 targeting may selectively inhibit cells with tumor-initiating or stem cell properties. EP4 antagonists can directly inhibit cancer stem cells and tumor metastasis and indirectly support NK-mediated mechanisms of tumor control. We are delineating the mechanisms by which EP4 and COX-2 are upregulated in cells with stem-like properties. In addition to EP4 and COX-2, STAT3 is upregulated in stem cells. Inhibition of STAT3 reduces mammosphere-forming capacity. Our studies support a mechanism whereby COX-2/EP4 signaling induces STAT3 to support breast cancer stem cell survival by a feed-forward mechanism. Citation Format: Amy Fulton, Namita Kundu, Tyler Kochel, Xinrong Ma, Jocelyn Reader. Prostaglandin E receptor EP4 is a therapeutic target in breast cancer stem cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-06-03.
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