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Inhibition of DNA Synthesis and Growth in Human Breast Stromal Cells by Bradykinin: Evidence for Independent Roles of B₁ and B₂ Receptors in the Respective Control of Cell Growth and Phospholipid Hydrolysis¹

Unit of Metabolic Medicine, St. Mary's Hospital Medical School, Imperial College of Science, Technology, and Medicine, London W2 1PG, United Kingdom

The paracrine and intracellular mechanisms controlling stromal cell growth in the normal or neoplastic breast are unknown. This in vitro study uses human breast fibroblasts to investigate a potential role for the inflammatory peptide mediator bradykinin (BK) in the regulation of DNA synthesis and signal transduction in these cells. Bradykinin stimulated a dose-dependent increase in inositol lipid hydrolysis and cytosolic Ca²⁺ levels in serum-starved fibroblasts derived from both normal and breast tumor tissue. Bradykinin also caused a dose-dependent decrease in cell growth and [³H]thymidine incorporation into DNA in breast fibroblasts. Epidermal growth factor (EGF) and insulin-like growth factor 1 both stimulated DNA synthesis in breast fibroblasts. Bradykinin inhibited this mitogenic effect of EGF but not that due to insulin-like growth factor 1. The binding of ¹²⁵I-labeled EGF to fibroblasts was also inhibited by BK. Prostaglandin E₂ also inhibited fibroblast DNA synthesis, and the cyclooxygenase inhibitor indomethacin partially reversed the inhibitory action of BK on DNA synthesis. Studies with BK receptor antagonists and agonists indicate that inositol lipid signalling and arachidonic acid mobilization in response to BK are B₂ receptor-mediated pathways, whereas the inhibition of DNA synthesis appears to be via B₁ receptors. Although these data support a role for prostaglandins and EGF receptor down-modulation in the inhibitory action of BK on DNA synthesis in breast fibroblasts, a B₁ receptor-mediated pathway is also implicated. This study highlights a potential pathophysiological role for BK as a negative regulator of breast stromal cell growth.

¹ This work was supported by a grant from the Cancer Research Campaign, United Kingdom.

² To whom requests for reprints should be addressed.

Received 7/22/91. Accepted 10/31/91.

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