Crosstalk between steroid receptors and the c-Src-receptor tyrosine kinase pathways: implications for cell proliferation

Both steroids and growth factors stimulate proliferation of steroid-dependent tumor cells, and interaction between these signaling pathways may occur at several levels. Steroid receptors are typically classified as ligand-activated transcription factors, and steps by which they bind ligand, dimerize, recruit coregulatory molecules, and activate target gene transcription are well understood. Several steroid responses are functionally linked to c-Src or tyrosine kinase receptors, and the physiological impact and the precise molecular pathways involved in these responses are under intensive investigation. Ligand-independent stimulation of steroid receptor-mediated transcription by growth factors is now believed to occur through activated protein kinases that phosphorylate the receptors and receptor coregulators. Recently, steroid hormones themselves have been shown to rapidly activate intracellular signaling cascades, via binding to cognate cytoplasmic or membrane-associated receptors. In some contexts, steroid receptors interact directly with c-Src and other cytoplasmic signaling molecules, such as Shc, PI3K, and p130 Cas. Crosstalk between growth factors and steroids in both the cytoplasm and nucleus could have profound impact on complex biological processes such as cell growth, and play a significant role in the treatment of steroid-dependent cancers. The potential roles of progesterone and estrogen receptors in this crosstalk are discussed in this review.