A Wnt-ow of Opportunity: Targeting the Wnt/beta-Catenin Pathway in Breast Cancer
Department of Surgery, University of Chicago, Chicago, IL 60637, USA. Current drug targets
(Impact Factor: 3.02).
Aberrant activation of the Wnt/beta-catenin signaling pathway is a hallmark of many tumors, including breast cancer. In the normal breast, tightly regulated expression of Wnt/beta-catenin pathway components, including Wnts and the APC tumor suppressor, dictates its role in balancing stem cell self-renewal, maintenance and differentiation during embryonic and postnatal development. Therefore, not surprisingly, dysregulation of Wnt/beta-catenin signaling through overexpression of pathway activators, such as Wnts or stabilized beta-catenin, or targeted disruption of inhibitors, such as APC, leads to mammary tumorigenesis in several genetically engineered mouse (GEM) models. These models are powerful tools to dissect the importance of Wnt/beta-catenin signaling in human breast cancer because they recapitulate some of the histological features of human breast cancers that demonstrate pathway dysregulation. Over the last decade, numerous approaches have been developed to target the Wnt/beta-catenin pathway in tumor cells, from antagonizing Wnt ligand secretion or binding to promoting beta-catenin degradation to specifically blocking beta-catenin-mediated transcriptional activity. Despite sizeable hurdles because of gaps in our knowledge of most efficacious ways to inhibit the pathway, the breast cancer subtypes to target and how pathway antagonists might be used in combination therapy, crippling Wnt/beta-catenin signaling offers a tremendous opportunity to impact breast cancer pathogenesis. This review will provide an overview of the current understanding of Wnt/beta-catenin pathway involvement in regulating normal breast development and morphogenesis, the generation of Wnt/beta-catenin-dependent GEM models of human breast cancer, upregulation of signaling in human breast cancers and the compelling therapeutic strategies aimed at targeting the Wnt/beta-catenin pathway that show promising anti-tumor activity.
Available from: Tsung-Teng Huang
- "Previous reports have indicated that activation of the Wnt/β-catenin signaling pathway is crucial for the maintenance of CSCs in leukemia , breast cancer , melanoma , colorectal adenoma , and liver cancer . This cellular pathway also regulates self-renewal, proliferation, and differentiation of cancer stem-like cells in gastric cancer . "
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ABSTRACT: Cancer stem cells (CSCs) represent a unique sub-population of tumor cells with the ability to initiate tumor growth and sustain self-renewal. Although CSC biomarkers have been described for various tumors, only a few markers have been identified for nasopharyngeal carcinoma (NPC). In this study, we show that CD24+ cells isolated from human NPC cell lines express stem cell genes (Sox2, Oct4, Nanog, Bmi-1, and Rex-1), and show activation of the Wnt/β-catenin signaling pathway. CD24+ cells possess typical CSC characteristics that include enhanced cell proliferation, increased colony and sphere formation, maintenance of cell differentiation potential in prolonged culture, and enhanced resistance to chemotherapeutic drugs. Notably, CD24+ cells produce tumors following inoculation of as few as 500 cells in immunodeficient NOD/SCID mice. CD24+ cells further show increased invasion ability in vitro, which correlates with enhanced expression of matrix metalloproteinase 2 and 9. In summary, our results suggest that CD24 represents a novel CSC biomarker in NPC.
Available from: Michael Klüppel
- "Aberrantly activated Wnt/beta-catenin signaling has been associated in a number of human diseases and malignancies, including cancer, fibrosis, and cardiovascular disease , , , , , . Thus, much effort has gone into the identification and characterization of Wnt pathway inhibitors, although translation of this research into clinical applications has not been successful thus far , , , . Our previous results, together with the results presented here, suggest that the CS biosynthesis machinery could be an important pharmacological target to control aberrant Wnt/beta-catenin signaling in a number of biological and pathological systems, including cardiovascular disease. "
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ABSTRACT: The glycosaminoglycan chondroitin sulfate is a critical component of proteoglycans on the cell surface and in the extracellular matrix. As such, chondroitin sulfate side chains and the sulfation balance of chondroitin play important roles in the control of signaling pathways, and have a functional importance in human disease. In contrast, very little is known about the roles of chondroitin sulfate molecules and sulfation patterns during mammalian development and cell lineage specification. Here, we report a novel biphasic role of chondroitin sulfate in the specification of the cardiac cell lineage during embryonic stem cell differentiation through modulation of Wnt/beta-catenin signaling. Lineage marker analysis demonstrates that enzymatic elimination of endogenous chondroitin sulfates leads to defects specifically in cardiac differentiation. This is accompanied by a reduction in the number of beating cardiac foci. Mechanistically, we show that endogenous chondroitin sulfate controls cardiac differentiation in a temporal biphasic manner through inhibition of the Wnt/beta-catenin pathway, a known regulatory pathway for the cardiac lineage. Treatment with a specific exogenous chondroitin sulfate, CS-E, could mimic these biphasic effects on cardiac differentiation and Wnt/beta-catenin signaling. These results establish chondroitin sulfate and its sulfation balance as important regulators of cardiac cell lineage decisions through control of the Wnt/beta-catenin pathway. Our work suggests that targeting the chondroitin biosynthesis and sulfation machinery is a novel promising avenue in regenerative strategies after heart injury.
Available from: Kathleen H Goss
- "While studies have investigated targeting the upstream components of the Wnt/-catenin pathway, such as Wnt ligands and DVL (reviewed in ), these approaches would have minimal effect in APC-mutant cancers. Therefore , potentially successful therapeutic treatments for these tumors should target components of the Wnt pathway downstream of APC, and will be the focus of this review (summarized in Table 1). "
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ABSTRACT: The Adenomatous Polyposis Coli (APC) tumor suppressor is most commonly mutated in colorectal cancers such as familial adenomatous polyposis (FAP); as well as many other epithelial cancers like breast, pancreatic, and lung cancer. APC mutations usually result in a truncated form of the protein lacking the carboxy-terminal region resulting in loss of function. Mutations in APC have been identified in early stages of cancer development making it a gatekeeper of tumor progression and therefore an ideal therapeutic target. APC is best known for its role as a negative regulator of the Wnt/β -catenin pathway. However, APC also mediates several other normal cell functions independently of Wnt/β-catenin signaling such as: apical-basal polarity, microtubule networks, cell cycle, DNA replication and repair, apoptosis, and cell migration. Given the vast cellular processes involving APC, the loss of these "normal" functions due to mutation can contribute to chemotherapeutic resistance. Several therapeutic treatments have been explored to restore APC function including the reintroduction of APC into mutant cells, inhibiting pathways activated by the loss of APC, and targeting APC-mutant cells for apoptosis. This review will discuss the normal functions of APC as they relate to potential treatments for patients, the role of APC loss in several types of epithelial cancers, and an overview of therapeutic options targeting both the Wnt-dependent and -independent functions of APC.
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