Scatter factor (also known as hepatocyte growth factor) is a glycoprotein secreted by stromal cells that stimulates cef motility and proliferation. In vitro, scatter factor stimulates vascular endotheHal cell migration, proliferation, and organization into capillary-like tubes. Using two different in vivo assays, we showed that physiologic quantities ofpurified native mouse scatter factor and recombinant human hepatocyte growth factor induce angiogenesis (the formation of new blood vessels). The angiogenic activity was blocked by specific anti-scatter factor antibodies. Scatter factor induced cultured microvascular endothelHal cells to accumulate and secrete signiflcantly increased quantities of urokinase, an enzyme associated with development of an invasive endothelial phenotype during angenesis. We further showed that immunoreactive scatter factor is present surrounding sites of blood vessel formation in psorlatic skin. These findings suggest that scatter factor may act as a paracrine miator in pathologic angiogenesis aociated with human inflammatory disese.

The BRCA1 gene was previously found to inhibit the transcriptional activity of the estrogen receptor [ER-a] in human breast and prostate cancer cell lines. In this study, we found that breast cancer-associated mutations of BRCA1 abolish or reduce its ability to inhibit ER-a activity and that domains within the amino-and carboxyltermini of the BRCA1 protein are required for the inhibition. BRCA1 inhibition of ER-a activity was demonstrated under conditions in which a BRCA1 transgene was transiently or stably over-expressed in cell lines with endogenous wild-type BRCA1 and in a breast cancer cell line that lacks endogenous functional BRCA1 (HCC1937). In addition, BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D. The BRCA1 protein was found to associate with ER-a in vivo and to bind to ER-a in vitro, by an estrogen-independent interaction that mapped to the amino-terminal region of BRCA1 (ca. amino acid 1-300) and the conserved carboxyl-terminal activation function [AF-2] domain of ER-a. Furthermore, several truncated BRCA1 proteins containing the amino-terminal ER-a binding region blocked the ability of the full-length BRCA1 protein to inhibit ER-a activity. Our ®ndings suggest that the aminoterminus of BRCA1 interacts with ER-a, while the carboxyl-terminus of BRCA1 may function as a transcriptional repression domain. Oncogene (2001) 20, 77 ± 87.

Mutations of the breast cancer susceptibility gene BRCA1 confer increased risk for breast, ovarian, and prostatic cancers, but it is not clear why the mutations are associated with these particular tumor types. In transient transfection assays, BRCA1 was found to inhibit signaling by the ligand-activated estrogen receptor (ER-alpha) through the estrogen-responsive enhancer element and to block the transcriptional activation function AF-2 of ER-alpha. These results raise the possibility that wild-type BRCA1 suppresses estrogen-dependent transcriptional pathways related to mammary epithelial cell proliferation and that loss of this ability contributes to tumorigenesis.