PROSTAGLANDIN E(2) PRODUCTION AND METABOLISM IN HUMAN BREAST-CANCER CELLS AND BREAST FIBROBLASTS - REGULATION BY INFLAMMATORY MEDIATORS

Malignant human breast rumours contain high levels of prostaglandin E(2) (PGE(2)). However, the mechanisms controlling PGE(2) production in breast cancer are unknown. This in vitro study investigates the capacity for PGE(2) synthesis and metabolism in several human breast cancer cell lines and early passage human breast fibroblasts and seeks to identify potential regulatory factors which may control these pathways. Basal PGE(2) production rose up to 30-fold in breast fibroblast lines on addition of exogenous arachidonic acid (10 mu M), whereas no such changes were observed in six out of seven cancer cell lines, with the exception of modest increases in MDA-MB-231 cells. Interleukin 1 beta (IL-1 beta) also induced PGE(2) production in breast fibroblasts in the presence of excess substrate, consistent with cyclo-oxygenase induction by the cytokine. Under these conditions only Hs578T cells and MDA-MB-231 cells demonstrated large increases in PGE(2) in response to IL-1 beta or phorbol ester; no such responses were seen in MCF-7, T47-D, ZR-75-1, BT-20 or CLF-90-1 cells. In the absence of added arachidonate, bradykinin (BK) and endothelin-l (ET-1), potentiated PGE(2) production in IL-1 beta-treated fibroblasts, possibly by mobilising endogenous substrate. PGE(2) also stimulated ET-1 production by breast cancer cells. In co-cultures with T47-D cells both basal and stimulated PGE(2) production by breast fibroblasts was greatly reduced. This appeared to be due to metabolic inactivation by the cancer cell since T47-D cells readily converted PGE(2) to 15-keto-PGE(2). This apparent 15-hydroxy-PG dehydrogenase activity was stimulated by TPA and inhibited by cycloheximide. In conclusion, breast fibroblasts, particularly under the influence of inflammatory mediators, provide a potentially rich source for PGE(2) production in breast tumours, whereas significant contributions from the epithelial tumour component may be restricted to cancer cells exhibiting an invasive phenotype. Metabolic inactivation by the cancer cells may also play an important role in the regulation of breast tumour PGE(2) levels.