Abstract : Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are widely-distributed stimuli of cellular growth and functions, which are generated enzymatically from precursors in membranes of activated normal cells and at much higher levels from many types of cancers. A subfamily of 0 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,-S, -6, and -8). Human breast cancer cells (BCCs) express principally Edg-3, less Edg-4, very low levels of Edg-2 and Edg-5, and no Edg-1, -6,-? or -8. BCCs have much higher levels of Edg-3 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 BCCs secretion of several autocrine protein growth factors. 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 Rs and splice variants of Edg-3 Rs may become a diagnostic index of breast cancer and Edg R- directed antagonists may suppress growth and dissemination of breast cancers.