Molecular Mechanisms of Estrogens in the Induction of Epithelial-to-Mesenchymal Transition and Metastasis in Breast Cancer.

Estrogens have been widely shown to induce cell proliferation in breast cancer (BC) cells. Recently, we have described their involvement in the induction of epithelial-mesenchymal transition (EMT), migration, and invasion. The aim of this work is to review the molecular mechanisms by which estradiol (E) activates different signaling pathways, both genomic and non-genomic, through binding to different estrogen receptors (ERs), depending on the phosphorylated amino acid (Ser-118 or Tyr-537). The relevance of the present work lies in the molecular details of c-Src kinase activation by the membrane estrogen receptor (mER) and its effects on the early and late phases of EMT. This process initiates a loss of cell adhesion, leading to migration, which culminates in metastasis of cancer cells to distant tissues. Understanding how estrogens induce metastasis will facilitate the development of better strategies to counteract the lethality of BC. Finally, the quantification of Snail may serve as a molecular marker in the early stages of tumor progression, as well as the use of drugs against c-Src and ERs, as they may be therapeutic targets.