NF-KAPPA-B ACTIVATION AND INTERLEUKIN-6 PRODUCTION IN FIBROBLASTS BY ESTROGEN RECEPTOR-NEGATIVE BREAST-CANCER CELL-DERIVED INTERLEUKIN-1-ALPHA

Several angiogenic factors and extracellular matrix-degrading enzymes that promote invasion and metastasis of cancer are produced by stromal fibroblasts that surround cancer cells. The expression of genes that code for some of these proteins is regulated by the transcription fact or NF-kappa B. In this report, we demonstrate that conditioned medium (CRI) from estrogen receptor (ER)-negative but not ER-positive breast cancer cells induces NF-kappa B in fibroblasts. In contrast, CM from b oth ER-positive and ER-negative breast cancer cells induces NF-kappa B in macrophages and endothelial cells. NF-kappa B activation in fibrob lasts was accompanied by induction of interleukin 6 (IL-6) and urokina se plasminogen activator (uPA), both of which promote angiogenesis and metastasis. A survey of cytokines known for their ability to induce N F-kappa B identified IL-1 alpha as the factor responsible for NF-kappa B activation in fibroblasts. Analysis of primary breast carcinomas re vealed the presence of IL-1 alpha transcripts in majority of lymph nod e-positive breast cancers. These results along with the known role of IL-1 alpha and IL-6 in osteoclast formation provide insight into the m echanism of metastasis and hypercalcemia in advanced breast cancers.