Repression of the Estrogen Receptor-α Transcriptional Activity by the Rho/Megakaryoblastic Leukemia 1 Signaling Pathway

Although involved in processes leading to the emergence and development of hormone-dependent breast cancers, the estrogen receptor alpha (ER alpha) also prevents transformed cells from progressing toward a more aggressive phenotype. The transcriptional activity of ER alpha is mediated through two transactivation functions, called activation function 1 and 2, whose respective involvement varies in a cell-specific manner. Here, we identify the Rho/megakaryoblastic leukemia 1 (MKL1) signaling pathway as a main actor in controlling the cell-specific activity of both transactivation functions of ER alpha. Notably, we show that, when the coregulator MKL1 is sequestered in an inactive form by unpolymerized actin, the transcriptional activity of ER alpha mainly relies on the activation function 1. The activation of MKL1, which results from its dissociation from unpolymerized actin, promoted by the ability of Rho to support polymeric actin accumulation, silences the activation function 1 of ER alpha and allows the receptor to mainly act through its activation function 2. Importantly, this switch in the respective contribution exerted by both transactivation functions is correlated with an impaired ability of ER alpha to efficiently transactivate estrogen-regulated reporter genes. MKL1 is further shown to be present on estrogen-responsive genes in vivo. Interestingly, the Rho/MKL1 signaling pathway is activated during the epithelial-mesenchymal transition. A reduced transactivation efficiency of ER alpha, resulting from the activation of this pathway, may therefore suppress the protective role exerted by ER alpha toward tumor progression and invasiveness.