Candidate prognostic markers in breast cancer: focus on extracellular proteases and their inhibitors

Abstract

The extracellular matrix (ECM) is the complex network of proteins that surrounds cells in multicellular organisms. Due to its diverse nature and composition, the ECM has a multifaceted role in both normal tissue homeostasis and pathophysiology. It provides structural support, segregates tissues from one another, and regulates intercellular communication. Furthermore, the ECM sequesters a wide range of growth factors and cytokines that may be released upon specific and well-coordinated cues. Regulation of the ECM is performed by the extracellular proteases, which are tasked with cleaving and remodeling this intricate and diverse protein matrix. Accordingly, extracellular proteases are differentially expressed in various tissue types and in many diseases such as cancer. In fact, metastatic dissemination of tumor cells requires degradation of extracellular matrices by several families of proteases, including metalloproteinases and serine proteases, among others. Extracellular proteases are emerging as strong candidate cancer biomarkers for aiding and predicting patient outcome. Not surprisingly, inhibition of these protumorigenic enzymes in animal models of metastasis has shown impressive therapeutic effects. As such, many of these proteolytic inhibitors are currently in various phases of clinical investigation. In addition to direct approaches, aberrant expression of extracellular proteases in disease states may also facilitate the selective delivery of other therapeutic or imaging agents. Herein, we outline extracellular proteases that are either bona fide or probable prognostic markers in breast cancer. Furthermore, using existing patient data and multiple robust statistical analyses, we highlight several extracellular proteases and associated inhibitors (eg, uPA, ADAMs, MMPs, TIMPs, RECK) that hold the greatest potential as clinical biomarkers. With the recent advances in high-throughput technology and targeted therapies, the incorporation of extracellular protease status in breast cancer patient management may have a profound effect on improving outcomes in this deadly disease.

Role of the Tumor Microenvironment in Breast Cancer

“…fibronectin) and proteoglycans (e.g. chondroitin sulfate) [64]. While initially regarded as a stable structure solely providing support, newer studies indicate that the ECM is surprisingly dynamic and versatile, and represents a key player in cellular processes such as cell growth, proliferation and migration [64,65].…”

“…chondroitin sulfate) [64]. While initially regarded as a stable structure solely providing support, newer studies indicate that the ECM is surprisingly dynamic and versatile, and represents a key player in cellular processes such as cell growth, proliferation and migration [64,65]. The ECM is often disorganized and deregulated in cancer, leading to abnormal behavior of cells through feedback regulatory mechanisms [65].…”

“…Its integrity plays a key role in cancer development, since degradation of collagen IV by proteases leads to cancer cell invasion through the BM [66]. In addition to structural roles, the ECM also guides the passage of cytokines and growth factors between cells, thus enabling intercellular communication [64]. Extracellular proteinases such as MMP maintain homeostasis of the ECM and are a second important key player in the tumor microenvironment.…”

“…Altered proteinase activity is prevalent in cancer and shows an association with patient outcome [65]. In view of this, several extracellular proteinase inhibitors are in development for use in human cancer [64]. While synthetic MMP inhibitors have shown efficacy against malignant tumors in preclinical studies, the outcomes of clinical MMP inhibitor trials exceeding phase II have been disappointing [67].…”

Matrix metalloproteinases as drivers and therapeutic targets in breast cancer

“…At the level of transcription, analyses of large microarray patient datasets have identified MMP-1, -9, -12, -14, and -15 as predictive of adverse outcome in one dataset comprised of primary tumors from 295 patients (33, 34), and MMP-9, -11, and -15 as associated with poor survival in another dataset of primary tumors from 1500 patients (35, 36). Neither of these studies identified associations of any MMPs with positive outcomes.…”