Matrix metalloproteinases (MMPs) degrade and modify the extracellular matrix (ECM) as well as cell-ECM and cell-cell contacts, facilitating detachment of epithelial cells from the surrounding tissue. MMPs play key functions in embryonic development and mammary gland branching morphogenesis, but they are also upregulated in breast cancer, where they stimulate tumorigenesis, cancer cell invasion and metastasis. MMPs have been investigated as potential targets for cancer therapy, but clinical trials using broad-spectrum MMP inhibitors yielded disappointing results, due in part to lack of specificity toward individual MMPs and specific stages of tumor development. Epithelial-mesenchymal transition (EMT) is a developmental process in which epithelial cells take on the characteristics of invasive mesenchymal cells, and activation of EMT has been implicated in tumor progression. Recent findings have implicated MMPs as promoters and mediators of developmental and pathogenic EMT processes in the breast. In this review, we will summarize recent studies showing how MMPs activate EMT in mammary gland development and in breast cancer, and how MMPs mediate breast cancer cell motility, invasion, and EMT-driven breast cancer progression. We also suggest approaches to inhibit these MMP-mediated malignant processes for therapeutic benefit.

We present the isolation and characterization of seven novel [natural] pyrroloiminoquinones, the makaluvamines A-F (1-6), makaluvone (7), and the known compounds discorhabdin A (8) and damirone B (9) from the Fijian sponge Zyzzya cf. marsailis. The makaluvamines exhibit potent in vitro cytotoxicity toward the human colon tumor cell-line HCT 116, show differential toxicity toward the topoisomerase II sensitive CHO cell-line xrs-6, and inhibit topoisomerase II in vitro. This activity may be mediated by intercalation into DNA and single-stranded breakage. Makaluvamine A and C exhibited in vivo antitumor activity against the human ovarian carcinoma Ovcar3 implanted in athymic mice. The makaluvamines suggest a plausible interrelationship between the batzelline/isobatzelline and discorhabdin/prianosin classes of compounds.f American Cyanamid Co.

Matrix metalloproteinases (MMPs) have been implicated in diverse roles in breast cancer development and progression. While many of the different MMPs expressed in breast cancer are produced by stromal cells MMP-9 is produced mainly by the tumor cells themselves. To date, the functional role of tumor cell-produced MMP-9 has remained unclear. Here, we show that human breast cancer cell-produced MMP-9 is specifically required for invasion in cell culture and for pulmonary metastasis in a mouse orthotopic model of basal-like breast cancer. We also find that tumor cell-produced MMP-9 promotes tumor vascularization with only modest impact on primary tumor growth, and that silencing of MMP-9 expression in tumor cells leads to an altered transcriptional program consistent with reversion to a less malignant phenotype. MMP-9 is most highly expressed in human basal-like and triple negative tumors, where our data suggest that it contributes to metastatic progression. Our results suggest that MMP9 may offer a target for anti-metastatic therapies for basal-like triple negative breast cancers, a poor prognosis subtype with few available molecularly targeted therapeutic options.

A classical peptide inhibitor of serine proteases that is hydrolyzed Ϸ10 7 times more slowly than a good substrate is shown to form an acyl-enzyme intermediate rapidly. Despite this quick first step, further reaction is slowed dramatically because of tight and oriented binding of the cleaved peptide, preventing acyl-enzyme hydrolysis and favoring the reverse reaction. Moreover, this mechanism appears to be common to a large class of tight-binding serine protease inhibitors that mimic good substrates. The arrest of enzymatic reaction at the intermediate stage allowed us to determine that the consensus nucleophilic attack angle is close to 90°in the reactive Michaelis complexes.