Role of Estrogens and Their Receptors in Adhesion and Invasiveness of Breast Cancer Cells

Summary

Estrogen receptors (ERs) are overexpressed in human breast cancers (BCs) and associated with differentiated tumors and with a more favorable prognosis. Paradoxically, ERs mediate the mitogenic action of estrogens in human BC cells and the efficacy of antiestrogens in adjuvant therapy of primary tumors. The exact mechanism underlying the ER protection against cancer progression to metastasis remains to be investigated. Herein, we show that ERs decrease invasiveness of BC cells. Detailed studies revealed that the unliganded and the E₂-activated ERs decrease cancer cell invasion in vitro through two distinct mechanisms. In the presence of ligand, ERα inhibits invasion through a mechanism requiring the functional ERα domains involved in the transcriptional activation of target genes. Moreover, using different approaches, we found that cell-cell contacts were markedly increased by 17β-estradiol (E₂) treatment and decreased by the pure antiestrogen, ICI_182,780. This cell-cell adhesion was associated with an increase of the major intercellular junctions, desmosomes. Conversely, in the absence of ligand, ERα also inhibits invasion through a distinct mechanism involving protein-protein interaction with the region of the first zinc finger of ERα. The relationship of these data with clinical studies and their potential therapeutic consequences will be discussed.