Open Life Sci. 2016; 11: 98–104 Topical Issue on Cancer Signaling, Metastasis and Target Therapy Open Access Review Article Quan Liang, Wei Li, Zhanchao Zhao, Qiang Fu* Advancement of Wnt signal pathway and the target of breast cancer DOI 10.1515/biol-2016-0013 cancer metastasis [3]. Upon activation, the Wnt signals Received April 24, 2016; accepted June 6, 2016 stabilize and lead to the accumulation of β-catenin. Abstract: Wnt/β-catenin signaling has been proved to Activated β-catenin dissociates with E-cadherin, play an important role in the development and promotion dissembling the adherens and activating expression of of cancer metastasis. The activation of Wnt signals target genes, most of which show invasion promotion can lead to duplicating, updating, metastasizing and functions [4]. The activation of Wnt signals leads to relapsing. The Wnt signaling pathway is mainly divided duplicating, updating, metastasizing and relapsing. into the Wnt/β-catenin pathway and the Wnt/calcium The Wnt signaling pathway is mainly divided into the pathway. A better understanding of all the diverse Wnt/β-catenin pathway and the Wnt/calcium pathway. functions of Wnt and their molecular mechanisms has An overview of the Wnt signaling pathway follows. evoked prevailing interest in identifying additional targets related to the Wnt /β-catenin pathways in breast cancer. A number of new target, related to Wnt /β-catenin 2 Wnt/β-Catenin Pathway pathways have been identified in recent years, including The TCF/LEF family of DNA-bound transcription NOP14, BKCa channels, Emilin2, WISP, MicroRNAs, factors participates in regulating the gene for β-catenin NRBP1, TRAF4, and Wntless. In this review, we will [5]. Binding of β-catenin to TCF/LEFs can activate introduce the new targets related to the Wnt /β-catenin or de-repress Wnt target genes [6]. TCF carry a single pathways in breast cancer. high motility group (HMG) domain, sufficient for DNA binding and an N-terminal β-catenin binding Keywords: Breast cancer, Wnt signal pathway, microRNA domain [5]. In addition, HMG can bind to destruction complexes, consisting of proteins including adenomatous polyposis coli (APC), glycogen synthase 1 Introduction kinase (GSK)-3β, casein kinase (CK)-1α and β-catenin, which are brought together by the scaffold [7]. Upon Breast cancer is the most common cancer and a leading binding to the destruction complex, β-catenin causes cause cancer-related death in females [1]. Although phosphorylation, followed by ubiquitination and improvements in understanding the underlying degradation by the proteasome, when Fz receptors mechanisms of breast cancer and developing new are unoccupied by Wnt ligands [8]. Therefore, without therapeutic approaches have been recently achieved, Wnt stimulation, cytoplasmic β-catenin levels are kept more than 400,000 women die from breast cancer every low by a degradation complex [9]. However, when Wnt year [2]. Wnt/β-catenin signaling has been shown to play binds to its receptors Frizzled and LRP, the destruction an important role in the development and promotion of complex cannot promote β-catenin signaling [10]. That state allows APC and axin binding to this membrane complex and prevents the breakdown of β-catenin, *Corresponding author: Qiang Fu, Department of General Surgery, therefore free unphosphorylated β-catenin can Tianjin Medical University General Hospital, Tianjin 300052, China, E-mail: [email protected] accumulate and translocate to the nucleus where it Quan Liang, Zhanchao Zhao, Department of General Surgery, Tianjin binds to transcription factors, including T-cell factor Medical University General Hospital, Tianjin 300052, China (TCF) and LEF-1 [11,12]. Wei Li, Department of Ultrasonography, Tianjin Medical University General Hospital, Tianjin 300052, China © 2016 Quan Liang et al., published by De Gruyter Open. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License. Advancement of Wnt signal pathway and the target of breast cancer 99 3 Wnt/Calcium Pathway into the nucleus of breast cancer cells. Additionally, in ER-positive breast cancers, NOP14 increase the level of Calcium signaling activity is sufficient to activate calcium ERα via NRIP1, implied that NOP14 can suppress breast sensitive enzymes, including protein kinase C (PKC), cancer by inhibiting the Wnt/ β-catenin pathways possibly calcium dependent kinase II (CamKII) or calcineurin by up-regulating NRIP1 [25]. These findings provide new (CaCN) [13]. PLC cleaves phosphatidylinositol-4, hope of developing targeted therapies against NOP14 and 5-bisphosphate (PIP2) into inositol-1, 4, 5- trisphosphate NRIP1 for breast cancer. (IP3) and diacylglycerol (DAG) [14]. IP3 binds to IP3 receptors, which release Ca2+ from subcellular stores such as the endoplasmic reticulum (ER) [15]. Activated 5 BKCa channel calcineurin dephosphorylates the transcription factor and The large conductance of calcium and voltage activated nuclear factor of activated T-cells (NFAT), allowing NFAT potassium (BKCa) channels function as oncogenes to translocate into the nucleus where it activates NFAT- in breast cancers [26]. Through gene amplification, responsive genes [16]. alternative splicing, and increased protein half-life, BKCa Based on a better understanding of all the diverse channels are overexpressed in many types of cancers [27- functions of Wnt and their molecular mechanisms in 30]. In glioma cells, BKCa channels are somewhat more recent years, additional targets associated with Wnt sensitive to calcium and voltage than other BK channels, signals pathway have been discovered. In this review, we and thus generate K+ currents in environments where their make a summary on these new targets. Investigating the normal counterparts are silent [27]. Higher grade tumors, protein and gene, which is associated with Wnt signals characterized by enhanced growth and invasiveness, pathway, will provide a theoretical basis for targeted express more BK channels than lower grade tumors treatment of breast cancer. [27]. BKCa channels generate vast amounts of outward K+ currents and therefore are powerful modulators of the transmembrane potential of a cell. The investigators 4 NOP14 observed that BKCa channels also function as oncogenes in β-catenin-positive breast cancer; they direct their NOP14 is a stress-responsive gene that is required for oncogenic input towards sustaining the tumorigenic 18S rRNA maturation and 40S ribosome production, ability of cancer cells; inhibitors of BKCa channels may interacting with PAXIP1, which plays a critical role in modulate in vitro tumorigenesis via transmembrane maintaining genome stability, condensation of chromatin depolarization. It is therefore plausible for BKCa channels and progression through mitosis, containing tandem to be considered putative targets for anticancer therapies. breast cancer carboxyl-terminal domains and regulating multiple aspects of the cellular response to DNA damage, such as cell survival and differentiation [17–22]. Recent 6 Emilin2 studies have suggested that NOP14 may be related to cancer development. In prostate cancer cells, NOP14, a Emilin2 is an extracellular matrix (ECM) protein that exerts target gene of the polycomb repressive complex, plays a antagonistic effects in the tumor microenvironment. By critical role in neoplastic progression [23,24]. Moreover, activating the extrinsic apoptotic pathway, Emilin2 affects high levels of NOP14 mRNA and protein were observed tumor cell viability [31,32]. It is directly up-regulated by in the fibrocystic breast cell line MCF10A; whereas the miR-320 and is part of a fibroblast secretome profile that levels of NOP14 mRNA and protein were low in the four correlates with clinical outcome in breast cancer patients breast cancer cell lines. Strikingly, NOP14 levels contrast [33,34]. The molecular regulations governed by Emilin2 with the malignancy of human breast cancer, which is in breast cancer have been investigated. Marastoni et high in atypical ductal hyperplasia (ADH) and primary al. identified Emilin2 as a novel molecular partner of cancer but low in the advanced breast cancer tissues. Wnt1 and demonstrated that this interaction led to a Importantly, the investigators discovered that NOP14 significant inhibition of the Wnt signaling pathway. could assemble β-catenin on the membranes of breast Emilin2 can halt the expression of β-catenin target genes cancer cells and prevent its nucleus translocation and through decreasing LRP6 phosphorylation and β-catenin the following activation. NOP14 increased APC and activation. They also observed that Emilin2 binds to β-catenin levels, as well as GSK-3β phosphorylation level Wnt1 and impairs Wnt signaling activation in vitro and in breast cancer cells, and inhibited the entry of β-catenin in vivo experiment. Therefore, Emilin2 can slow cell cycle 100 Q. Liang, et al. progression and reduce cell motility, impairing breast have concluded that WISP2 plays a dual role in the cancer cell growth and development [35]. These findings progression of breast and pancreatic cancer, acting as an reveal a further mechanism that Emilin2 suppresses oncogenic promoter at early stages of tumor development tumor growth, providing evidence of the key role of and subsequently, at later stages, as a suppressor of the microenvironment during tumor development and the invasive phenotype [48–50]. Corresponding studies reinforcing the therapeutic potential of this molecule. have suggested that less aggressive breast cancer cell lines highly