What does matrix metalloproteinase-1 expression in patients with breast cancer really tell us?

Mannello BMC Medicine 2011, 9:95 http://www.biomedcentral.com/1741-7015/9/95 COMMENTARY Open Access What does matrix metalloproteinase-1 expression in patients with breast cancer really tell us? Ferdinando Mannello Abstract Molecular and biochemical expressions of matrix metalloproteinases in breast cancer tissue and cells offers promise in helping us understand the breast cancer microenvironment, and also in the future it is hoped this will improve its detection, treatment and prognosis. In a retrospective study recently published in BMC Cancer, microenvironment predisposing to breast cancer progression, metastatic behavior and the expression of matrix metalloproteinase-1 (MMP-1) and its correlation with well-known biochemical, molecular and clinicopathologic factors in breast cancer cells and cancer-associated stromal cells was examined; this study also analyzed patient survival in different breast cancer subtypes. The positive correlation in breast tumor and stromal cells between MMP-1 expression and several markers of tumor grade and stage provide us with some useful new insights into important questions about the molecular profiling of the stromal microenvironment in metastatic breast cancer. The study showed that MMP-1 expression is strongly associated with poor clinical outcome, so now we look forward to future larger studies in breast cancer patients in which we can relate wider MMP molecular profiling to identify lethal tumor and stromal microenvironments predisposing to breast cancer progression, metastatic behavior and poor prognosis. Please see related article http://www.biomedcentral. com/1471-2407/11/348 Introduction Breast cancer (BC) is the most common cancer in women worldwide, comprising at least 16% of all female cancers. BC results from multiple environmental and hereditary risk factors, even though genetic traits, age Correspondence: Department of Biomolecular Sciences, Section of Clinical Biochemistry, Unit of Cell Biology, University ‘Carlo Bo’ of Urbino, I-61029 Urbino (PU), Italy and hormones are the main recognized BC-predisposing risk factors [1]. Human female BC encompasses a variety of tumors, which differ in their morphological, biochemical and molecular characteristics, all guiding clinical outcome and patient survival. Although welldocumented classic diagnostic/prognostic biomarkers/ profiles are reliable (for example, tumor grade and stage, p53, bcl-2, Ki-67, hormone receptor status,: human epidermal growth factor receptor 2 (HER-2) expression), there is the urgent need to differentiate between BC subclasses (for example, non-basal-like luminal A and B, basal-like, triple-negative BC)[2,3], patients with different prognoses and treatment responses to the same therapy [4-6]. Examining new BC biomarkers has proven that matrix metalloproteinases (MMP), which are zincdependent endopeptidases belonging to the Metzincin superfamily, are involved in several key events of both physiologic processes (for example, tissue remodelling, stem cell differentiation and proliferation, apoptosis) [7-11] and in pathological conditions (for example, inflammation, degeneration and cancer) [12-14]. The MMP family comprises several classes of proteases [15], which cleave almost all extracellular matrix components and a variety of proteins and growth factors crucial for neoplastic initiation and progression; these data suggest MMPs as good targets for tumor biomarker discovery. In humans, there are 24 MMP genes, but only 23 MMP proteins [16], including 17 soluble, secreted enzymes and 6 membrane-associated proteinases. MMPs are built up by a diverse structural domain architecture, and differ in their substrate specificity and in temporal and tissue specific expression patterns. MMPs were originally named for their preferred substrates within the extracellular matrix (ECM): collagen-cleaving MMPs (MMP-1, -8, and -13) were designated collagenases, gelatin (denatured collagen)-cleaving MMPs (MMP-2 and -9) were termed gelatinases, and MMPs degrading a broad spectrum of ECM proteins were called stromelysins (MMP-3, -10, © 2011 Mannello; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mannello BMC Medicine 2011, 9:95 http://www.biomedcentral.com/1741-7015/9/95 Page 2 of 7 and -11) or matrilysins (MMP-7). As the MMP family grew with the discovery of additional paralogs, including the membrane-associated MMPs, a numbering system was adopted, and MMPs are now grouped according to their domain structure (Figure 1). Many studies have characterized the increased expression of MMPs at both protein and mRNA levels, identifying them as a key event leading to the initiation/ progression of BC and linking them with the ability of cancer to metastasize. Thus, MMPs could be used as tumor biomarkers and indicators of cancer metastasis with diagnostic and prognostic usefulness [17,18]. On the other hand, recent evidence underlines the fact that some MMPs (such as MMP-8, also named collagenase-2 or neutrophil collagenase) may favor host defense instead of stimulating tumor proliferation, suggesting that these proteinases have an unexpected protective biological role in cancer processes [19,20]. Among the MMP members involved in BC, both the biochemical and molecular expression profile of MMP-1 (named also collagenase-1 or interstitial collagenase) have been extensively analyzed in human BC. Although there are a great number of valuable in vitro and in vivo studies concerning its role in breast carcinogenesis (see reviews [21-23]), some parts of its regulation and expression (as an assisting marker in metastatic BC diagnosis) remain poorly understood and a matter of debate [21,24,25]. Domains N S N C P Pro C S Pro S Pro N C MMPs C t Cat Zn Cat Zn Cat Zn MMPͲ7,Ͳ26 Hpx MMPͲ1,Ͳ3,Ͳ8,Ͳ10,Ͳ11,Ͳ12, , , , , , , Ͳ13,Ͳ19,Ͳ20,Ͳ21,Ͳ27,Ͳ28 Hpx MMPͲ2,Ͳ9 Fn N S N C C S Pro S Pro N Zn Pro F Cat C Cat Zn Cat Zn Hpx TM C Hpx p GPI CA Ig MTͲMMP1,2,3,5 (MMPͲ14,Ͳ15,Ͳ16,Ͳ24) MTͲMMP4,6 ( (MMPͲ17,Ͳ25) ) MMPͲ23 Figure 1 Domain structures of secreted and membrane-anchored MMPs. The basic organizations of human MMP family members are depicted: S, signal peptide; Pro, pro-peptide; Cat, catalytic domain, containing cysteine group (C);Zn, zinc ion; Fn, fibronectin-II- like repeats; Hpx, hemopexin like domain; TM, transmembrane domain; GPI, glycol-phosphatidylinositol membrane anchor; C, cytoplasm tail; CA, cysteine array; Ig, immunoglobulin-like domain; the flexible linker or hinge region is represented by a wavy black ribbon. The domain structure includes the signal peptide, which guides the enzyme into the endoplasmic reticulum during synthesis, the propeptide domain, which sustain (...truncated)