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Activation of Inositol Phospholipid Signaling and Ca²⁺ Efflux in Human Breast Cancer Cells by Bombesin¹

Department of Chemical Pathology, St. Mary's Hospital Medical School, London W2 1PG, United Kingdom

Members of the bombesin-related family of peptides (BRPs) are mitogenic for a variety of cell types; however, a role for these peptides has not been previously described in human breast cancer. Early membrane receptor signal transduction mechanisms associated with bombesin action include phospholipase C-mediated inositol phospholipid hydrolysis and the elevation of cytosolic Ca²⁺ levels. We have investigated a potential role for BRPs in breast cancer by studying their effect on phospholipid hydrolysis, ⁴⁵Ca²⁺ efflux, and cell growth in the human breast cancer cell line MCF-7. Bombesin stimulated a dose-dependent increase in the hydrolysis product inositol monophosphate during 1 h with a half-maximal effect around 1 nM. A transient increase in inositol trisphosphate in response to bombesin was also apparent at 2 min. Two distinct bombesin receptor antagonists inhibited this bombesin-induced phospholipid hydrolysis. Both bombesin- and gastrin-releasing peptide also stimulated a dose-related increase in inositol phosphate production in T47D cells, a different human breast cancer cell line. The efflux of ⁴⁵Ca²⁺ from prelabeled MCF-7 cells was also stimulated by bombesin. This apparent cellular Ca²⁺ mobilization was partly dependent on extracellular Ca³⁺ and was inhibited by Ni²⁺. Despite this activation of putative mitogenic signaling pathways, bombesin had no effect on either proliferation or DNA synthesis in MCF-7 cells. These data implicate a functional role for BRPs in human breast cancer.

¹ Supported by a grant from the Cancer Research Campaign. A preliminary communication of this work was presented at the 178th meeting of the Society for Endocrinology, 1988 (15).

² To whom requests for reprints should be addressed.

Received 5/ 2/89. Revised 10/ 5/89. Accepted 10/16/89.

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