Malignant human breast tumours contain high levels of
prostaglandin E2 (
PGE2). However, the mechanisms controlling
PGE2 production in
breast cancer are unknown. This in vitro study investigates the capacity for
PGE2 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
PGE2 production rose up to 30-fold in breast fibroblast lines on addition of exogenous
arachidonic acid (10 microM), 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
PGE2 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
PGE2 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-1 (ET-1), potentiated
PGE2 production in
IL-1 beta-treated fibroblasts, possibly by mobilising endogenous substrate.
PGE2 also stimulated ET-1 production by
breast cancer cells. In co-cultures with T47-D cells both basal and stimulated
PGE2 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
PGE2 to
15-keto-PGE2. 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
PGE2 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
PGE2 levels.