Lysophospholipid Receptors and Effects in Breast Cancer
Annual rept. 1 Jul 1999-30 Jun 2000
CALIFORNIA UNIV SAN FRANCISCO
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Lysophosphatidic acid LPA and sphingosine 1-phosphate S 1 P are widely-distributed growth factors generated enzymatically from membrane precursors in activated cells, which attain micromolar concentrations in plasma and tissue fluids. A subfamily of G protein-coupled receptors encoded by endothelial differentiation genes Edg Rs bind and transduce cellular signals from LPA Edg-2, -4, -7 and S1P Edg-l, -3, -5, -6, and -8. Human breast cancer cells BCCs express principally Edg-2 to -5, and low levels of Edg-7, but no Edg-1, -6 or -8. BCCS have higher levels of Edg-3 and -5 S1P Rs than normal human breast epithelial cells. These Edg Rs mediate proliferation of BCCs directly by signaling growth-related immediate-early genes through a distinctive set of transcription factors and indirectly by increasing BCC secretion of autocrine protein growth factors, such as the type II insulin-like growth factor. Delivery of LPA to BCCs by specific plasma protein carriers, such as gelsolin, and novel mechanisms for regulation of expression of Edg-3 Rs also may distinguish mechanisms of action of SIP and LPA in BCCs from those in normal breast epithelial cells. Detection of elevated levels of Edg-3 R may become a diagnostic index of breast cancer and Edg R-directed antagonists may suppress growth and dissemination of breast cancers.
- Medicine and Medical Research