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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: 3.6). 09/2010; 11(9):1074-88.
Source: PubMed

ABSTRACT 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.

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    • "While studies have investigated targeting the upstream components of the Wnt/-catenin pathway, such as Wnt ligands and DVL (reviewed in [151]), 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.
    Current drug targets 11/2013; 15(1). DOI:10.2174/1389450114666131108155418 · 3.60 Impact Factor
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    • "The Wnt signaling pathway plays a critical role in stem cell renewal, survival, and differentiation, as well as in the normal development and homeostasis of tissues including the mammary gland (Boras- Granic and Wysolmerski, 2008). De-regulation of Wnt signaling plays a causal role in breast cancer (reviewed in Prosperi and Goss, 2010). Aberrant Wnt signaling has been shown to play role in accelerating tumorigenesis by promoting CIN in the absence of p53 (Donehower et al., 1995) and numerous studies have implied that Wnt signaling is directly involved in mitotic regulation (reviewed in Niehrs and Acebron, 2012). "
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    ABSTRACT: Most solid tumors are characterized by abnormal chromosome numbers (aneuploidy) and karyotypic profiling has shown that the majority of these tumors are heterogeneous and chromosomally unstable. Chromosomal instability (CIN) is defined as persistent mis-segregation of whole chromosomes and is caused by defects during mitosis. Large-scale genome sequencing has failed to reveal frequent mutations of genes encoding proteins involved in mitosis. On the contrary, sequencing has revealed that most mutated genes in cancer fall into a limited number of core oncogenic signaling pathways that regulate the cell cycle, cell growth, and apoptosis. This led to the notion that the induction of oncogenic signaling is a separate event from the loss of mitotic fidelity, but a growing body of evidence suggests that oncogenic signaling can deregulate cell cycle progression, growth, and differentiation as well as cause CIN. These new results indicate that the induction of CIN can no longer be considered separately from the cancer-associated driver mutations. Here we review the primary causes of CIN in mitosis and discuss how the oncogenic activation of key signal transduction pathways contributes to the induction of CIN.
    Frontiers in Oncology 06/2013; 3:164. DOI:10.3389/fonc.2013.00164
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    ABSTRACT: While cancer treatment modalities are gradually improving due to increased knowledge about tumor heterogeneity and the cancer stem cell hypothesis, there remains a disconnect between tumor detection and mortality rates. The increasing knowledge of stem cell biology and its contribution to cancer progression illuminates the potential for chemopreventative regimens that effectively target the tissue-specific stem cell. Several signaling pathways have emerged that are critical for regulating stem cell self-renewal and multilineage differentiation over a range of tissue types, including Wnt, Hedgehog, and Notch signaling. Dysregulation of these genes can lead to cancer, which supports the cancer stem cell hypothesis. Several known chemopreventative agents have recently been shown to impact these and other pathways in the stem cell population, suggesting that their efficacies may be attributed in part to maintaining homeostasis of tissue-specific stem cells. Further understanding of the mechanisms of action of chemopreventative agents and of stem cell biology will generate better chemoprevention regimens that can be recommended especially to those in high-risk populations.
    Stem cell reviews 11/2010; 7(2):307-14. DOI:10.1007/s12015-010-9205-7 · 3.21 Impact Factor
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