The estrogen receptor alpha (ER alpha) is key in regulating normal breast development and function and is closely involved in the onset and progress of cancers. ER alpha transcriptional activity is mediated through two activation functions, AF1 and AF2, whose activity is tightly regulated in a cell-specific manner through yet unknown processes. Here, we demonstrate that cell-cell junctions generate cell permissiveness to AF1 through an up-regulation of the activity of an AF1 sub-region termed box 1. Moreover, the loss of E-cadherin expression is shown to silence the AF1 activity of ER alpha, allowing the receptor to mainly act through its AF2. This switch from an AF1 to an AF2 cell permissiveness also consequently results in the attenuation of ER alpha activity. Therefore, a loss of cell-cell junctions, a key process that occurs during the epithelial-mesenchymal transition, should have a broad impact on ER alpha transcriptional functions.