DHEAS prevents pro-metastatic and proliferative effects of 17ß-estradiol on MCF-7 breast cancer cells

Abstract It is generally assumed that circulating dehydroepiandrosterone sulfate (DHEAS) can be desulfated and further metabolized to estrogen, which is of concern for all patients with estrogen-responsive breast cancer. We addressed this issue by comparing the effects of DHEAS, its desulfated form DHEA, and 17s-estradiol on human metastatic, estrogen-responsive MCF-7 breast cancer cells. Physiological concentrations of DHEAS promoted phosphorylation of Erk1/2, whereas DHEA and 17s-estradiol failed to stimulate Erk1/2 phosphorylation, indicating that the sulfated steroid acts as an autonomous hormone. Exposure of MCF-7 cells to 17s-estradiol stimulated cell proliferation and the expression of pro-metastatic and pro-invasive elements such as claudin-1, matrix metalloproteinase 9 (MMP9), and the CC chemokine ligand 2 (CCL2). In contrast, treatment with DHEAS did not stimulate these responses but prevented all of the actions of 17s-estradiol, and as a consequence cell migration and invasion were completely inhibited. The results of this study not only challenge the assumption that DHEAS poses a danger as an endogenous source of estrogen, they rather favor the idea that keeping DHEAS levels within a physiological range might be supportive in treating estrogen-responsive breast cancer.