Exposure to sex steroids increases the risk of breast cancer, but the mechanisms are poorly understood. Angiogenesis is crucial in tumor development and progression. Very little is known about the regulation of angiogenesis in the normal breast. Vascular endothelial growth factor (VEGF) has a key stimulatory role in angiogenesis. Interferon-inducible protein 10 (IP-10) is a potent inhibitor of angiogenesis in vivo. These factors function in autocrine/paracrine pathways; therefore, direct measurements in the target tissue are needed. I measured VEGF and IP-10 in normal human breast tissue in situ in healthy women, using microdialysis, in the follicular and luteal phase of the menstrual cycle. In breast tissue, VEGF levels increased in the luteal phase, compared with the follicular phase (17.8 +/- 4 pg/ml to 34 +/- 9 pg/ml, P < 0.05). Plasma VEGF did not show a cyclic variation (10.6 +/- 2.8 pg/ml vs. 14.6 +/- 3.5 pg/liter, P = 0.3). IP-10 levels did not vary during the menstrual cycle either in breast tissue (65 +/- 17 pg/ml vs. 75 +/- 21 pg/ml, P = 0.6) or in plasma (64 +/- 7 pg/ml vs. 81 +/- 10 pg/ml, P = 0.06). The data suggests that, in the luteal phase, VEGF and IP-10, in the normal human breast, exhibit a proangiogenic profile. This may be one mechanism by which sex steroids contribute to breast cancer development.