Tumor cells react to hypoxia by adapting gene expression through the activation of the transcription factor hypoxia-inducible factor 1 (HIF-1). HIF-1 has been recognized to accelerate the progression and metastasis of mammary carcinomas. In vitro data have provided that nitric oxide (NO) can modulate the cellular oxygen-sensing process which controls HIF-1-dependent hypoxic gene activation. Thus the aim of this study was to examine the influence of the NO donor DETA-NO on tumor growth and metastasis in vivo using an autochthonous mouse model of breast carcinoma: transgenic mice overexpressing the polyoma virus middle T (PyMT) oncoprotein in mammary epithelial cells. After mice had developed palpable tumors they were injected every third day intra-peritoneally with DETA-NO or saline over a period of 4 weeks. Our data indicate that DETA-NO treatment resulted in higher tumor burden but decreased pulmonary metastasis. In addition, we studied PyMT transgenic mice with a conditional knock-out of the oxygen-sensitive HIF-1α subunit in tumor cells. Here, our data suggest that tumor onset is delayed for HIF-1α K.O. mice. Further analysis of immunohistochemistry and quantitative real-time PCR will elucidate the role of HIF-1 in NO-mediated tumor progression.