Interaction Between Estrogen Receptor-Beta and the Transforming Growth Factor-Beta Signaling Cascade in Human Breast Tissue

摘要

Breast tumorigenesis and breast cancer progression involves the deregulation and hyperactivation of intracellular signalling proteins that lead to uncontrolled cellular proliferation, invasion and eventually, metastasis. During breast cancer development, there is a marked upregulation of estrogen receptor-alpha (ERalpha)(l) expression levels that is accompanied by alterations in estrogen responsiveness. Within normal breast epithelium, the majority of proliferating cells are ERalpha negative(2), while in breast tumors it is the ERalpha positive cells that are associated with an increase in cellular proliferation and metastasis(3), suggesting that estrogen action changes from that of an indirect mitogen to a direct mitogen. Although the mechanism by which ER becomes deregulated during breast tumorigenesis and breast cancer progression is unknown, the fact that alterations in other factors that enhance ER activity also change during breast cancer development(4) may be an underlying factor. In addition to the ER, expression and cellular responses to the transforming growth factor-beta (TGFbeta) signalling pathway also change during breast tumorigenesis and breast cancer progression. For normal mammary epithelial cells, TGFbeta is a potent physiological inhibitor of cell cycle progression(5). In breast cancer, however, cells have lost their natural growth inhibitory response to TGFbeta and may become more aggressive and more likely to metastasize in the presence of this factor(6).