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Chapter category: Cancer Metastasis

Maspin Suppresses Breast Cancer Cell Invasiveness by Modulating Integrin Expression and Function

Chapter authors:
Richard E.B. Seftor, Valerie A. Odero, Elisabeth A. Seftor and Mary J.C. Hendrix

Although the novel tumor suppressor gene maspin (mammary serine protease inhibitor) was originally isolated from normal mammary epithelium by subtractive hybridization and differential display almost seven years ago,^1-2 it is still unclear how it functions molecularly and biologically to regulate tumor cell motility, invasion and metastasis.^1-3 The maspin protein has an M_r of 42,000 and contains sequence homology with members of the serine protease inhibitor superfamily (serpins), including plasminogen activator inhibitor-1, -2 (PAI-1 and PAI-2) and a1-antitrypsin, as well as sequence homology with noninhibitor serpins, such as ovalbumin.³ This apparent dual nature of maspin is consistent with the observations that while recombinant maspin can act at the cell membrane to inhibit cell migration and invasion and requires an intact reactive site loop, it can also function as a substrate rather than an inhibitor for a number of different serine proteases (e.g., tissue- and urokinase-type plasminogen activators; tPA and uPA).^3-8 When acting as a serine protease inhibitor in vitro, maspin binds specifically to purified single chain tPA (sctPA) activated to cleave plasminogen to plasmin and results in biphasic effects on sctPA. This suggests a complex interaction between maspin and sctPA which could contribute to the regulation of plasminogen activation by sctPA when bound to the epithelial cell surface.⁹ Recently, recombinant maspin was shown to inhibit plasminogen activation to plasmin associated with uPA activity (but not tPA activity) at the cell surface of the prostate carcinoma cell line DU-145. This correlated quantitatively with maspin's inhibition of cell motility in vitro.¹⁰ There has also been a recent report that maspin is regulated by p53 in breast and prostate cancer cells lines.^{11, 12} This suggests that maspin and p53 cooperate in the negative regulation of tumor cell invasion and metastasis. Taken together, these observations indicate that maspin may play a significant role in regulating processes that are associated with the progression and metastatic cascade of certain cancers (e.g., breast and prostate cancer), and could thereby present an unique and specific target for the diagnosis and therapeutic intervention of these cancers.

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