Blockade of Tumor Cell TGF-Betas: A Strategy to Reverse Antiestrogen Resistance in Human Breast Cancer

摘要

Transforming growth factor beta (TGF beta) is a pleiotropic growth factor, which plays a critical role in modulating cell growth, differentiation and plasticity. There is increasing evidence that after transformed cells lose their sensitivity to TGF beta-mediated growth inhibition, autocrine TGF Beta signaling may potentially promote tumor cell motility, invasiveness, and metastatic progression. In order to understand the molecular mechanisms by which autocrine TGF beta may selectively contribute to tumor cell progression, we have performed a series of studies using mouse and human mammary tumor cells. Collectively, these studies indicate that signaling by phosphatidylinositol-3 kinase (PI3K), Akt, and p38 Mapk are required for TGF Beta-mediated epithelial- to-mesenchymal transition (EMT) and cell motility. In addition, Smad signaling does not appear to be involved in these processes, in that forced expression of Smad 2/4 and Smad 3/4 at levels adequate to induce robust TGF Beta reporter activity, failed to induce EMT and cell migration. Therefore, Smad signaling does not appear to be involved in the tumor-promoting effects of signaling by the TGF Beta network. Furthermore, PI3K, Akt, and p38 Mapk represent rational molecular targets for treatment approaches aimed at interfering with the tumor promoting effects of the TGF betas.