Metastasis suppressors and their roles in breast carcinoma

Abstract

Metastasis remains the most deadly aspect of cancer and still evades direct treatment. Clinically and experimentally, primary tumor development and metastasis are distinct processes-locally growing tumors can progress without the development of metastases. The discovery of endogenous molecules that exclusively inhibit metastasis suggests that metastasis is an amenable therapeutic target. By definition, metastasis suppressors inhibit metastasis without inhibiting tumorigenicity and are thus distinct from tumor suppressors. As the biology underlying functional mechanisms of metastasis suppressors becomes clearer, it is evident that metastasis suppressors could be harnessed as direct drug targets, prognostic markers, and to understand the fundamental biology of the metastatic process. Metastasis suppressors vary widely in their cellular localization: they are found in every cellular compartment and some are secreted. In general, metastasis suppressors appear to regulate selectively how cells respond to exogenous signals, by affecting signaling cascades which regulate downstream gene expression. This review briefly summarizes current functional and biochemical data on metastasis suppressors implicated in breast cancer. We also present a schematic integrating known mechanisms for these metastasis suppressors highlighting potential targets for therapeutic intervention.

Figure 1

Schematic of proposed signaling by metastasis suppressors. Blue (dark) shapes indicate metastasis suppressors and red (light) shapes indicate signaling molecules. Black (dark) arrows indicate positive regulation and red (light and stunted) connections represent negative regulation. Cellular location of metastasis suppressors is according to currently known data. Only those biochemical pathways and interactions that have been experimentally confirmed are depicted, however, not all signaling pathways are shown (see text for details).