Effects of estradiol and progestogens on tumor-necrosis factor--induced changes of biochemical markers for breast cancer growth and metastasis

Background. Epidemiological data suggest an enhanced breast cancer risk during estrogen/progestogen therapy as compared to estrogen monotherapy in postmenopausal women. The underlying mechanism, however, still remains unknown. Estrogens are known to be mitogenic agents for benign and cancerous breast epithelial cells whereas the role of progestogens is unclear. Tumor-associated macrophages play a crucial role in tumor growth and metastasis due to the synthesis of various cytokines such as tumor necrosis factor- (TNF-), which can stimulate the synthesis of proliferative and angiogenic factors in tumor cells. In an invitro model we investigated the influence of estradiol and estradiol/progestogens combinations on the changes of TNF-- induced markers. Methods. MCF-7 cells, a human estrogen- and progesterone-receptor-positive human breast cancer cell line, were used for the experiments. Estradiol (E2), at a concentration of 0.1 nM, and the progestogens progesterone (P), norethisterone (NET) and medroxyprogesterone acetate (MPA), each at concentrations of 0.01 to 1M, were tested alone and in combination. The cells were incubated for 4 days and the markers monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) were measured in the supernatant by enzyme-linked immunosorbent assay. Results. E2 in combination with TNF- elicited significant increases in MCP-1 and VEGF concentrations compared with TNF- alone. For the progestogens alone an increase of MCP-1 was observed for NET, whereas MPA induced a decrease. An increase of VEGF was observed for all progestogens, the effect being greatest for MPA. No changes were found for MMP-9. In combinations with E2, the E2-induced increase of MCP-1 was reduced by NET and MPA and the increase of VEGF was diminished by P and NET, but not by MPA. The E2-induced decrease of MMP-9 was not antagonized by P and NET, but completely abolished by MPA. Conclusion. Our results indicate that E2 may have a stimulating effect on pre-existing tumor growth and metastasis. This effect seems to be influenced by progestogens in a different manner. Thus the choice of progestogen addition to estrogen therapy may be important, especially since different effects can occur in the case of pre-existing tumor cells.