Molecular Pathways: Targeting Steroid Receptor Coactivators in Cancer

Coactivators represent a large class of proteins that partner with nuclear receptors and other transcription factors to regulate gene expression. Given their pleiotropic roles in the control of transcription, coactivators have been implicated in a broad range of human disease states, including cancer. This is best typified by the three members of the steroid receptor coactivator (SRC) family, each of which integrates steroid hormone signaling and growth factor pathways to drive oncogenic gene expression programs in breast, endometrial, ovarian, prostate, and other cancers. Because of this, coactivators represent emerging targets for cancer therapeutics, and efforts are now being made to develop SRC-targeting agents, such as the SI-2 inhibitor and the novel SRC stimulator, MCB-613, that are able to block cancer growth in cell culture and animal model systems. Here, we will discuss the mechanisms through which coactivators drive cancer progression and how targeting coactivators represent a novel conceptual approach to combat tumor growth that is distinct from the use of other targeted therapeutic agents. We also will describe efforts to develop next-generation SRC inhibitors and stimulators that can be taken into the clinic for the treatment of recurrent, drug-resistant cancers.