Estrogen and antiestrogens alter breast cancer invasiveness by modulating the transforming growth factor-β signaling pathway

In the later stages of breast cancer, estrogen receptor (ER)alpha-negative cancers typically have higher histological grades than ER alpha-positive cancers, and transforming growth factor (TGF)-beta promotes invasion and metastasis. Our previous study indicated that ER alpha inhibited TGF-beta signaling by inducing the degradation of Smad in an estrogen-dependent manner. In the present study, we report that the suppressive effects of ER alpha and estrogen on tumor progression are mediated by inhibiting TGF-beta signaling. Furthermore, we investigated the effects of antiestrogens such as ICI182,780 (ICI) or tamoxifen (TAM) on TGF-beta signaling and breast cancer invasiveness. The levels of total Smad and pSmad were reduced by estrogen, whereas ICI slightly increased them, and TAM had no effect. To investigate the effect of antiestrogens on breast cancer invasiveness, we generated highly migratory and invasive MCF-7-M5 cells. The migration and invasion of these cells were suppressed by the inhibitor of TGF-beta receptor kinase, SB-505124, and estrogen. However, antiestrogens did not suppress the migration and invasion of these cells. In addition, we screened TGF-beta target genes whose expression was reduced by estrogen treatment and identified four genes associated with breast cancer invasiveness and poor prognosis. The expression of these genes was not decreased by antiestrogens. These observations provide a new insight into estrogen function and the mechanisms underlying estrogen-mediated suppression of tumor progression. (Cancer Sci 2011; 102: 1501-1508)