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Breast cancer progression may be affected by various cellular components expressed by the tumor cells and/or by microenvironmental factors. Many studies report the correlation between breast cancer progression and monocyte infiltration into the tumor site. We have identified recently the CC chemokine regulated on activation, normal T cell expressed and secreted (RANTES), a major monocyte chemoattractant expressed by breast tumor cells, as a potential contributor to breast cancer progression. In the present study, analysis of the regulation of RANTES expression demonstrates that the expression of RANTES in breast tumor cells is elevated significantly and in a synergistic manner by IFN-gamma and tumor necrosis factor-alpha. Identification of the mechanisms by which RANTES may contribute to breast cancer progression included the analysis of the potential ability of RANTES to act in paracrine and indirect mechanisms, as well as directly on the tumor cells, to promote disease progression. Our results suggest that breast tumor cell-derived RANTES may promote breast cancer progression by its partial contribution to monocyte migration into breast tumor sites. Moreover, RANTES promotes the expression of matrix metalloproteinase (MMP) 9 by THP-1 monocytic cells and elevates vascularity in chick chorioallantoic membrane assays. Tumor necrosis factor-alpha, a major monocyte-derived cytokine, was found to promote the expression of MMP9 and MMP2 by MCF-7 and T47D breast adenocarcinoma cells, respectively, and to induce the de novo expression of an additional proteolytic enzyme by T47D cells, presumably MMP9. The possibility that RANTES may act directly on breast tumor cells was supported by detection of the expression of the CCR5 RANTES receptor in biopsy sections of breast cancer patients and by the ability of RANTES to promote the expression of MMP9 by MCF-7 cells. In all, our study suggests that the expression of RANTES by breast tumor cells results not only in monocyte migration to the tumor site but also in protumorigenic activities of RANTES and of proinflammatory cytokines that may facilitate metastasis formation and contribute to disease progression.