Epigenetic Dysregulation of Maspin (SerpinB5) in Cancer Invasion and Metastasis

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Abstract

The goal of this chapter is to promote the value of studying maspin regulation as a paradigm for loss of transcriptional control during cancer progression and to highlight the importance of this endeavor in developing a comprehensive picture of the epigenetics of the malignant phenotype. We will attempt to do this through a discussion of the structure and functions of the serpin superfamily of proteins, with an emphasis on maspin, its discovery as a tumor suppressor, and its functional role in cancer. The control of maspin expression in normal tissue by epigenetic mechanisms will be described and how this underlying mechanism is compromised in cancer leading to the inappropriate silencing of maspin in cancers derived from maspin-positive cell types, as well as the activation of maspin in cancers derived from normally maspin-negative cell types. Finally, we will close with speculation that maspin may represent an inaugural member of a class of cell-type restricted genes involved in cancer cause and progression that are controlled by epigenetic mechanisms. During transformation, epigenetic instability and mischief results in a loss of control in the expression of these genes. We propose that these genes, through metastable epigenetic switching mechanisms, can be turned off and on in response to environmental stresses and cues in the cancer cell, thereby allowing tumor cells a phenotypic plasticity that appears necessary for the challenges a tumor cell and its progeny must undertake to migrate from primary tumor site to distant metastatic site. It is proposed that this epigenetic switch can be targeted by therapeutics designed to transcriptional reprogram tumor cells and flip the switch back to non-malignant behavior.