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Loss of E--Dependent Cell– and the Development and Progression of Cancer

Heather C. Bruner1 and Patrick W.B. Derksen2

1Department of Medicine, University of California at San Diego, La Jolla, California 92093 2Department of Pathology, University Medical Center Utrecht, Utrecht 3584CX, The Netherlands Correspondence: [email protected]

Classical are the key molecules that control cell–cell adhesion. Notwithstanding this function, it is also clear that classical cadherins are more than just the “glue” that keeps the cells together. Cadherins are essential regulators of tissue homeostasis that govern mul- tiple facets of cellular function and development, by transducing adhesive signals to a complex network of signaling effectors and transcriptional programs. In cancer, cadherins are often inactivated or functionally inhibited, resulting in disease development and/or progression. This review focuses on E-cadherin and its causal role in the development and progression of breast and gastric cancer. We provide a summary of the biochemical conse- quences and consider the conceptual impact of early (mutational) E-cadherin loss in cancer. We advocate that driven by E-cadherin loss should be considered “actin-dis- eases,” caused by the specific disruption of the E-cadherin-actin connection and a subse- quent dependence on sustained actomyosin contraction for tumor progression. Based on the available data from mouse and human studies we discuss opportunities for targeted clinical intervention.

INTRODUCTION two families is based on the presence of a distinct histidine-alanine-valine (HAV) sequence in the lassical cadherins aretransmembrane-span- first EC domain, which is important for cad- Cning adhesion molecules containing five herin engagement (Ozawa et al. 1990; Williams calcium-dependent extracellular (EC) domains et al.2002).Intotal, fivetype Iclassical cadherins that confer homotypic interactions and a cyto- can be defined based on the above criteria. While plasmic tail that bindsto a numberof effectorsto their names were initially based on the cell transduce physical and biochemical signals to type in which expression was first described, a the cell (reviewed in Lecuit and Yap 2015). Ver- consensus nomenclature now defines the classi- tebrate classical cadherins can be separated into cal cadherins as CDH1 (E-cadherin), CDH2 two related families; the type I and type II cad- (N-cadherin), CDH3 (P-cadherin), CDH4 (R- herins (Nollet et al. 2000). Specification of the cadherin), and CDH15 (M-cadherin) (Table 1).

Editors: Carien M. Niessen and Alpha S. Yap Additional Perspectives on Cell–Cell Junctions available at www.cshperspectives.org Copyright # 2018 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a029330 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a029330

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H.C. Bruner and P.W.B. Derksen

Table 1. Classical Type I cadherins. Nomenclature, genomic position, and cancer role Trivial name symbol Gene location Role in cancer References E-cadherin CDH1 (Cdh1) 16q22.1 (8:10.66Mb) Tumor Berx et al. 1995; Guilford et al. 1998; suppressor Perl et al. 1998; Derksen et al. 2006 N-Cadherin CDH2 (Cdh2) 18q12.1 (18:16.58Mb) Oncogene Islam et al. 1996; Hazan et al. 1997a P-cadherin CDH3 (Cdh3) 16q22.1 (8:10.65Mb) Multiple Radice et al. 1997; Peralta Soler et al. 1999; Paredes et al. 2004 R-cadherin CDH4 (Cdh4) 20q13.33 (2:17.94Mb) Tumor Agiostratidou et al. 2009 suppressor M-cadherin CDH15 (Cdh15) 16q24.3 (8:122.84Mb) Tumor Cool and Jolicouer 1999; Yamada et al. suppressor 2007 Information in parentheses depicts nomenclature (Gene symbol) or chromosomal positioning (Gene location) for Mus musculus. Mb¼Megabase.

Togetherwith the EC domains, the cytosolic duced morphological changes when forcing tail of E-cadherin forms the core of a mechano- these cells to grow in tight clusters under calci- transduction and signaling hub called the adhe- um-dependent conditions (Nagafuchi et al. rens junction (AJ), which connects intercellular 1987). Knockout studies subsequently showed contacts to the actin and microtubule cytoskel- that E-cadherin was essential for development, eton (reviewed in Leckband and de Rooij 2014). by showing that homozygous inactivation of For these functions, classical cadherins depend Cdh1 in mice led to embryonic lethality caused on the , which are essential mediators of by a failure of trophectoderm formation (Larue force and biochemical signals. Most proximal to et al. 1994). the intracellular face of the cell membrane, cad- Within this review we will focus on the role herins bind to p120- (CTNND1) (Ireton of E-cadherin in breast and gastric cancer, be- et al. 2002; Davis et al. 2003; Nanes et al. 2012), cause in contrast to the other type I cadherins, which was originally identified as a substrate of there is causal and clinically relevant evidence oncogenic Src (Reynolds et al. 1989). Cadherin that E-cadherin functions to repress tumor de- association with p120-catenin (p120) is essen- velopment and progression in these cancer types tial for stabilization and function of the classical (Berx et al. 1995; Guilford et al. 1998; Perl et al. cadherin (Reynolds et al. 1994; Yap et al. 1998; 1998; Derksen et al. 2006). Also, the down- Ireton et al. 2002; Davis et al. 2003; Nanes et al. stream effectors controlled by E-cadherin might 2012). Linkage of classical cadherins to the actin not be identical amongst the type I classical is enabled through binding to cadherins. Hence, this review will emphasize CTNNB1(b-catenin).Althoughthe exactwork- the observations made in breast cancer due ing mechanism underlying actin linkage still to the overwhelming data that depict a tumor remains uncertain, it appears that monomeric development and invasion suppressor role for a-catenin (CTNNA1) binds to b-catenin to link E-cadherin in this malignancy. the AJ to filamentous (F)-actin, whereas di- meric a-catenin associates directly with the ac- E-CADHERIN IS ESSENTIAL FOR MAMMARY tin cytoskeleton independently of the cadherin GLAND FORM AND FUNCTION (reviewed in Meng and Takeichi 2009 and Sha- piro and Weis 2009). The mammary gland mainly consists of two cell Evidence for a direct function of E-cadherin types; apical luminal epithelial cells that pro- in cell–cell adhesion was provided when the duce milk and basal myoepithelial cells that pro- full-length cDNA of E-cadherin was cloned vide a linkage to the mammary stroma and fa- and expressed in fibroblasts that do normally cilitate milk excretion during lactation. Next to not express E-cadherin. This experiment in- these major cell types the mammary gland also

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contains specialized (luminal) lobulo-alveolar dence points toward a basal and P-cadherin cells and likely two progenitor cell types expressing progenitor cell responsible for mam- that either control mammary gland formation mary formation and branching morphogenesis and/or hormone-dependent alveolar develop- (see Fig. 1), whereas alveolar progenitor cells ment (reviewed in Regan and Smalley 2007). probably are luminal-type cells giving rise to Cadherin expression in the differentiated cells E-cadherin positive decedents (reviewed in Vis- of the mammary gland is well-defined and cell- vader and Stingl 2014). Conditional inactiva- type specific (Fig. 1). E-cadherin is expressed by tion in the mammary gland using knockout luminal epithelial cells, whereas the myoepithe- mouse models has shown that E-cadherin is es- lial cell express P-cadherin (Daniel et al. 1995). sential for this organ. E-cadherin loss resulted in Expression of either cadherin in the progenitor luminal cells undergoing apoptosis and clear- or mammary stem cell populations, however, ance (Boussadia et al. 2002; Derksen et al. 2011). is still unclear, mainly because the exact In line with the differential cadherin expres- identity and architectural positioning of these sion, it was shown that inhibition of P-cadherin elusive cells remains ill-defined. Current evi- using neutralizing resulted in a par-

AB Mammary branching IDC tumor invasion

Mammary duct Terminal end bud Tumor mass Invasive front

BM/Laminin ECM ECM Luminal epithelial cell (E-cadherin, CK8/18) Luminal cancer cell (E-cadherin, CK8/18)

Myoepithelial cell (P-cadherin, CK5/14) Basal-type leader cell (E/P-cadherin, CK5/14)

Stem or progenitor cell Tumor-initiating/cancer stem cell Body cell (E-cadherin) CAP cell (P-cadherin)

Figure 1. Mammary gland development and breast cancer invasion. (A) Epithelial lineage commitment during mammary gland development. Shown is a schematic representation of a mammary duct with its differentiated myoepithelial (white cells) and luminal epithelial (gray) cells. The TerminalEnd Bud (TEB) is a structure at the leading front of a branching mammary structure during postnatal development. Here, both cell lineages are presumably generated through cell populations called “Cap cells” and “Body cells,” which express either P- cadherin and/or E-cadherin, respectively. Myoepithelial cells are basal in origin and produce laminins that constitute the basement membrane (BM; brown line). The enigmatic mammary stem or progenitor (black) cells may reside in the TEB and/or the resting mammary duct. Myoepithelial and luminal cell markers are indicated. (B) A scenario for late (epigenetic) inactivation of invasive ductal breast cancer (IDC). Cartoon depicting an invasive breast cancer strand mostly expressing luminal markers such as cytokeratin (CK) 8 and E-cadherin. Recent studies have highlighted the potential importance of focal (and transient?) acquisition of basal charac- teristics, which might underpin epigenetic E-cadherin inactivation leading to invasion and metastasis.

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H.C. Bruner and P.W.B. Derksen

tial but specific disruption of the basal cells in (ILC) was characterized by E-cadherin defi- the developing mammary gland (Daniel et al. ciency, whereas most other breast cancer sub- 1995). Subsequent genetic knockout studies types expressed E-cadherin. Genetic evidence in mice revealed that although P-cadherin- identified inactivating somatic CDH1 muta- deficient mice were viable and fertile, the result- tions in approximately 50% of all ILC samples ing female mice showed precocious alveolar analyzed (Berx et al. 1995,1996). Interestingly, differentiation and mammary hyperplasia, apart from ILC, half of all diffuse gastric carci- especially after multiple pregnancies (Radice nomas (DGC) analyzed also harbored somatic et al. 1997). Neither mammary-specific E-cad- inactivating CDH1 mutations (Muta et al. 1996; herin nor P-cadherin knockout mice developed Becker et al. 1994). Follow-up studies subse- tumors (Radice et al. 1997; Boussadia et al. quently identified germline inactivating E-cad- 2002; Derksen et al. 2011). Mammary-specific herin mutations in DGC (Guilford et al. 1998) inactivation and the resulting induction of and ILC (Masciari et al. 2007), suggesting a apoptosis in luminal cells showed that (1) E- unique and potential overlapping tumor etiol- cadherin loss is not tolerated in the mammary ogy of these two cancer types. gland (Boussadia et al. 2002; Derksen et al. E-cadherin-inactivating mutations in gas- 2011) and as such is an unlikely candidate driver tric cancer preferentially cause in-frame dele- event in tumor development; and (2) luminal tions caused by skipping of exons 7 or 9, or mammary cells lack a functional redundant occasional frameshift mutations, whereas the cadherin to compensate for E-cadherin loss. majority of somatic E-cadherin mutations in This is of interest because E-cadherin inactiva- ILC leads to frame shift mutations and muta- tion in postnatal skin is tolerated because of P- tions inducing premature stops in the extracel- cadherin redundancy (Tinkle et al. 2004; Tung- lular domain (Berx et al. 1998). Alternatively, gal et al. 2005), implying a tissue-specific and other cancer types such as prostate, endometri- context-dependent role for E-cadherin in the um, and invasive ductal (IDC) that mammary gland. In short, we propose that a show loss of E-cadherin expression, re- protumorigenic event that overrides the apo- tain a wild-type genetic makeup, but display ptotic signals induced by E-cadherin loss has methylation of the E-cadherin promoter (re- to precede or coincide with inactivation of the viewed in Strathdee 2002). In contrast to other wild-type CDH1 allele, which is a frequent event key tumor suppressors, no specific hotspots in multiple cancer types (reviewed in Strumane have been identified in the extracellular E-cad- et al. 2004). herin domain. This, together with the fact that E-cadherin silencing in ILC is caused by a com- bination of frameshift mutations and loss of LOSS OF E-CADHERIN UNDERPINS heterozygosity (LOH) (reviewed in Berx and TUMOR DEVELOPMENT AND Van Roy 2009), suggest that complete E-cad- PROGRESSION herin loss provides cancer cells with an evolu- At the end of the previous century it became tionary advantage over protein downregulation apparent that the pivotal role of E-cadherin dur- or functional aberrations. Furthermore, nonin- ing normal epithelial function might form the vasive lobular carcinoma in situ (LCIS) precur- basis for its function as a tumor suppressor. In sor lesions already showed loss of E-cadherin landmark papers by the Birchmeier and VanRoy protein expression (Vos et al. 1997), which is groups, it was shown that inhibition of E-cad- occasionally accompanied by contained germ- herin function was sufficient to induce dissoci- line loss of function mutations (Petridis et al. ation and invasion of cancer cells (Behrens et al. 2014), indicating that this loss is an early event 1985,1989; Vleminckx et al. 1991). Moll et al. in lobular cancer. (1993) subsequently showed clinical relevance In 1998, causal evidence that E-cadherin by demonstrating that a major breast cancer loss drives tumorigenesis was provided in vivo subtype called invasive lobular carcinoma using the Rip1TAG2 mouse model of pancreatic

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cancer (Dahl et al. 1996). In this model inhibi- E-CADHERIN LOSS AND THE EPITHELIAL tion of E-cadherin function using a dominant- TO MESENCHYMAL TRANSITION negative version that lacked most of the extra- cellular domains induced invasion and metas- E-cadherin expression is mostly restricted to tasis, whereas forced expression of full length epithelial cells, whereas cells of neural or mes- E-cadherin reversed the invasive phenotype enchymal origin usually express N-cadherin. (Perl et al. 1998). Although this experiment Epithelial cells are phenotypically dissimilar did not shed light on the intracellular conse- from mesenchymal cells; from a cancer point quences of E-cadherin loss in DGC and ILC, it of view the latter are more motile and migratory. elegantly showed that E-cadherin was an essen- Because the epithelial to mesenchymal cell tran- tial tumor progression suppressor in pancreatic sition (EMT) is an essential hallmark of embry- cancer. However, it took another 8 years to di- onic development, the idea was postulated by rectly link E-cadherin loss to the development leading cancer biologists that epithelial cancers of ILC. Using tissue-specific mouse models, it must acquire mesenchymal characteristics for was shown that stochastic and somatic E-cad- invasion and metastasis (reviewed in Kalluri herin inactivation in the mammary gland in and Weinberg 2009 and Nieto et al. 2016). combination with loss of p53 led to the forma- Although it appears obvious that an epithelial tion and progression of mouse ILC (Derksen cancer cell must attain specialized traits to in- et al. 2006, 2011). Concomitant loss of p53 vade and metastasize, it is less clear-cut what the was necessary because (1) E-cadherin loss biochemical and cell-receptor prerequisites of alone is not tolerated in the mouse mammary such a cell should be. In breast cancer a “cad- gland (Boussadia et al. 2002); and (2) condi- herin-switch” has been the focus of many labo- tional p53 knockout in the mammary gland ratories. Cadherin switching in cancer is de- induces formation of noninvasive mammary fined as loss of E-cadherin and expression of carcinomas (Liu et al. 2007; Derksen et al. N-cadherin during tumor progression (re- 2011), a prerequisite for studying tumor pro- viewed in Hazan et al. 2004), which will induce gression. A similar setup later established E- or enhance the metastatic capacity of the invad- cadherin loss as a driver of hereditary DGC ing carcinoma cell. Based on a preponderance of (HDGC), by showing that combined loss of E- experimental evidence, a consensus definition cadherin and p53 in the gastric lineage using was promoted, stating that a classical EMT Atp4b-Cre mice induced GDC development, should conform to the basic criteria of cadherin tumor invasion, and metastasis (Shimada switching and the acquisition of additional et al. 2012). A recent CRISPR/Cas9-based tu- mesenchymal markers (e.g., expression of Fi- mor progression experiment by the Jonkers bronectin and Vimentin). Despite the over- group elegantly showed that dual E-cadherin whelming experimental data that support a and PTEN inactivation also led to ILC develop- role for EMT phenomenon in cancer cell inva- ment and progression (Annunziato et al. 2016), sion and metastasis, evidence supporting EMT indicating that either inactivation of p53 or ac- as a clinically relevant driver of cancer metasta- tivation PI3K-dependent signaling synergizes sis is nonetheless scarce (Diepenbruck and with E-cadherin loss in ILC formation and pro- Christofori 2016). Classical EMT was also ab- gression. Supporting this are studies showing sent from tumors or their metastases in the that endogenous expression of the oncogenic above described mouse models of ILC and H1047R Pik3ca mutant in mice leads to luminal DGB (Derksen et al. 2006, 2011; Shimada features in ER-expressing mammary carcinoma et al. 2012). Apart from the obvious EMT hall- (Van Keymeulen et al. 2015). mark (E-cadherin loss), metastatic cells in these In conclusion, it is clear that loss of E-cad- models retained their epithelial characteristics herin is causal to tumor development and pro- based on luminal cytokeratin expression pat- gression in cancer, most notably in ILC and terns, and lacked expression of the mesenchy- HDGC. mal EMT markers. These findings conform to

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clinicopathological findings in DGC and ILC, In short, epigenetic silencing of E-cadherin where invading cells and their metastases are is likely driven by specific transcriptional pro- luminal epithelial-type cancer cells (Vlug et al. grams and appears to be a late event in cancer, 2013a; Mahmud et al. 2015; van der Post et al. whereas loss of E-cadherin and subsequent in- 2015). In sum, these data demonstrate that early activation of the wild-type allele represent an mutational loss of E-cadherin does not lead to a early driver of specific tumor development classical EMT. and progression. It therefore suggests that In contrast, invasive ductal cancer (IDC) the biochemical wiring of these two inactivation represents .95% of all non-ILC breast cancers mechanisms, as well as their functional and and is mostly E-cadherin positive (Molland phenotypic consequences are different, and et al. 2004). It is therefore apparent that loss of that the resulting malignancies should be clini- E-cadherin is not a driver event in IDC but in- cally treated as such. stead occurs late in tumor progression. This secondary E-cadherin loss can be caused by the ever-growing list of miRNAs, and transcrip- ALTERNATIVE AND INDIRECT MECHANISMS TO SILENCE E-CADHERIN tional repressors such as Slug and Snail (Nieto IN CANCER and Cano 2012). Hence, in IDC, the timing of E-cadherin inactivation and its consequences A causal relationship between E-cadherin loss for the underlying and resulting and the development of ILC or HDGC is not phenotype are clearly different when compared always overtly obvious. For example, approxi- to cancers that are driven by E-cadherin loss mately 5%–10% of lobular breast cancer cases such as HDGC and ILC. As mentioned previ- retain E-cadherin expression despite the pheno- ously, clinical evidence demonstrates that most typical ILC appearance (Rakha et al. 2010; IDCs appear to express E-cadherin at the inva- Canas-Marques and Schnitt 2015). Moreover, sive front (Moll et al. 1993). However, it is pos- 50% of all ILC cases show loss of E-cadherin sible that the invading leader cells temporally expression in the absence of inactivating down regulate E-cadherin, or are subjected to CDH1 mutations (Dabbs et al. 2007; Christgen EMT-type mechanisms that cause up-regula- and Derksen 2015). Because approximately tion of many other proinvasive molecules such 50%–70% of the affected HDGC families as P-cadherin (Albergaria et al. 2011). Indeed, show no evidence of a CDH1 inactivating mu- recent data by the Ewald laboratory have sug- tation, it is likely that other pathogenic variants gested that local induction of a basal-type tran- may be present in as yet unidentified DGC-as- scriptional program in breast cancers such as sociated susceptibility (Oliveira et al. IDC may underpin invasion and metastasis 2006; Kaurah et al. 2007). It thus appears that (Cheung et al. 2013). In the case of IDC this mechanisms other than genetic and epigenetic would imply that invasive leader cells are spa- silencing of E-cadherin contribute to aberrant tiotemporally reprogrammed to inappropriate- E-cadherin expression and subsequent impair- ly use their intrinsic mammary capacity to ment of AJ function. transdifferentiate between epithelial and mes- enchymal cell types (reviewed in Regan and Identification of a-catenin as an ILC Smalley 2007), a feature that might be governed and HGDC tumor suppressor by microenvironmental cues (Chen et al. 2013; Di-Cicco et al. 2015) (see Fig. 1B). These inter- A likely secondary mechanism that induces AJ esting insights will require a comprehen- dysfunction and a subsequent constitutive de- sive specification, follow-up, and functional regulation of actin function is a-catenin loss. characterization of the adhesion receptors in- Studies in breast cancer cell lines have shown volved to delineate the involvement of luminal that bi-allelic mutational inactivation of to basal transdifferentiation in breast cancer CTNNA1 is the underlying cause of dysfunc- progression. tional AJs. As a result, cells show a noncohesive

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cellular phenotype similar to lobular breast can- notype with mesenchymal/sarcomatoid and cer cells (Hazan et al. 1997b; Hollestelle et al. metaplastic features. Follow-up studies showed 2010). These findings were complemented by that p120 loss was dominant over E-cadherin the identification of germline truncating inactivation, because mammary-specific triple CTNNA1 mutations (with no evidence for knockout of p120, E-cadherin and p53 in CDH1 inactivation) in HDGC (Majewski et al. whey acidic protein (WAP) Cre recombinase- 2013). Interestingly, we have obtained prelimi- driven female mice promoted the development nary experimental evidence that a-catenin loss of basal, EMT-type metastatic mammary tu- in E-cadherin proficient breast cancer cell lines mors (Tenhagen et al. 2016). induces Rho/Rock-dependent anchorage inde- pendence and tumor progression of conditional p53-deficient mammary progenitors in vivo, Potential roles for junctional complexes other than the AJ in the maintenance of similar to E-cadherin inactivation (De Groot cell–cell adhesion and tutor suppression et al. unpubl.). Together, these findings imply that silencing of a-catenin represents an infre- Tight junctions (TJs) regulate adhesion and ep- quent but driving event that mimics E-cadherin ithelial permeability, a barrier feature that is of- loss and leads to AJ dysfunction and subsequent ten disturbed in cancer (reviewed by Martin cellular responses including constitutive Rock- et al. 2014). TJs are located apically from AJs dependent actin polymerization, in human and at the border of the apical and basolateral mem- mouse ILC alike. brane domains of epithelial cells. These junc- tions consist of transmembrane such as and that determine the AJ loss-of-function on p120 leads to a barrier properties of these junctions, and cyto- mesenchymal-type invasive tumor type solic linker proteins such as Zonula Occludens As mentioned previously, p120 is essential for (ZO) proteins and Cingulin that provide link- the stabilization and function of classical cad- age to the actin cytoskeleton and indirectly con- herins (Yap et al. 1998; Davis et al. 2003) (also nect the TJs and AJs (see Furuse 2010 for de- see Fig. 2A). Similar to E-cadherin loss, p120 tailed information). Maturation of the TJ is inactivation in the mammary gland is not tol- regulated by cytosolic mediators of polarity; erated and leads to apoptosis and sloughing of aPKC, PAR3, and PAR6 (Suzuki and Ohno mammary ductal epithelial cells (Kurley et al. 2006). Although it is unclear whether TJ genes 2012). Given the impact of a-catenin loss on are mutationally inactivated in breast cancer, junctional integrity and the potential outcome several TJ proteins were found to be down-reg- in cancer, one might assume a similar result on ulated or absent in advanced tumors. Interest- inactivation of p120. Surprisingly, p120 knock- ingly, analogous to E-cadherin, absence of out in the skin, oral cavity, esophagus, and squ- -7 (CLDN7) is evident in both LCIS amous forestomach does not seem to require and ILC and correlates with histological grade p53 inactivation and induced either hyperplasia in IDC (Kominsky et al. 2003; Sauer et al. 2005), or squamous cancer types in these tissues (Stairs suggesting a role in tumor development and et al. 2011; Perez-Moreno et al. 2008). To cir- progression. Likewise, expression of Zona Oc- cumvent the induction of apoptosis in the cludens 1 (ZO1; TJP1) was found to be reduced mammary gland, somatic p120 loss was com- or lost in the majority of breast cancers and bined with p53 knockout, which resulted in correlated with reduced E-cadherin staining overt mammary carcinoma invasion and metas- (Hoover et al. 1998), thus suggesting tumor tasis when compared to p53 inactivation alone suppressor activity. Since TJ components have (Schackmann et al. 2013). Interestingly, al- also been found overexpressed in certain malig- though p120 showed a clear role in suppression nancies, there is currently no consensus on how of invasion, tumors that developed were not TJ members are involved in tumor development lobular but instead displayed an EMT-like phe- and progression. However, recent evidence

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A B

E-cadherin GF GF

? Wnt11 GFR GFR

p120 P P P P   P X P P Merlin Merlin

 RhoA X Ras PI3K p120 Ras PI3K  P Cytosol Mrip Yap Yap

Rac1 RhoA Cytosol Rock P Erk Akt Erk Akt P Actin dynamics Proliferation/survival Actomyosin contraction P FOXO

Kaiso TEAD FOXO p120 Kaiso Yap Nucleus Balanced gene regulation X Wnt11 TEAD X BMF/BIM Nucleus

Aberrant transcription

Normal tissue homeostasis Anchorage-independent tumor growth/survival

Figure 2. Biochemical, transcriptional and phenotypical consequences of mutational E-cadherin in cancer. (A) E-cadherin and the (AJ) control epithelial homeostasis through a balanced regulation of actin dynamics, gene regulation and proliferation/survival. The simplified cartoon depicts the main players involved. First, the AJ connects the cell membrane to the actin cytoskeleton through intricate control of a cadherin, catenin and RhoGTPase interplay at the cell cortex and in the cytosol. Second, growth factor receptor (GFR) signaling and YAP-dependent proliferation is dampened by NF2/Merlin, which is complexed with the AJ. Finally, transcriptional repression by Kaiso and modulation by FOXO is tightly regulated caused by the presence of homeostatic AJ and GFR reciprocity. (B) Early mutational inactivation of E-cadherin cancer leads to oncogenic stimuli. Upon AJ dismantling, p120 translocates to the cytosol where it binds and inactivates myosin phospha- tase Rho-interacting Protein (MRIP), leading to derepression of RhoA and Rock. In contrast, b-catenin is uncoupled and largely degraded by the proteasome, whereas a-catenin resides in the cytosol as dimer. The functional role in cancer of the latter event is as yet undefined. Uncoupled p120 also translocates to the nucleus to bind to and relieve transcriptional repression by Kaiso, leading to expression of specific target genes. In case of Wnt11, this promotes autocrine activation of RhoA. Together, this drives constitutive low level actomyosin contraction in E-cadherin mutant cancer cells. AJ loss also leads to cytosolic retention and a conformational change in NF2/Merlin, an event that results in derepression and/or hypersensitization of growth factor (GF)- induced activation of the GFR. Concomitant with the Rock-induced actomyosin contraction, uncoupling (and phosphorylation?) of NF2/Merlin leads to activation of YAPand TEAD-mediated transcriptional activation of its gene targets. Finally, increased GFR signals hyperactivate RAS/MAP Kinase and PI3K/AKT signals. Phos- phorylation of AKT inhibits FOXO, leading to cytosolic retention and repression of FOXO-dependent tran- scription of the proapoptotic BMF and BIM. Altogether, these activated signals (depicted with red arrows) are oncogenic in E-cadherin mutant cells and control anchorage-independent tumor growth and survival, ulti- mately leading to tumor cell metastasis.

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showed that inhibition of the TJ-associated po- cogenic properties (reviewed in Dusek and At- larity protein PAR3 in mice enhanced invasion tardi 2011). For example, DSG2, DSG3, or and metastasis of oncogene-induced breast can- PKP3 expression was found to be increased in cer (Xue et al. 2012; McCaffrey et al. 2012). In several cancer types and correlated with reduced these studies PAR3 inhibition did not induce a patient survival (Furukawa et al. 2005; Chen classical EMT,but clearly attenuated E-cadherin et al. 2007; Brennan and Mahoney 2009). In expression and AJ stability. However, in the con- contrast, reduction or loss of expression of sev- text of oncogenic RAS, PAR3 loss led to a more eral DS components (DSG1-3; DSC2 and basal and cytokeratin 14-expressing tumor cell DSC3; JUP and PKP1-3) has been linked to ad- type (McCaffrey et al. 2012), supporting a lu- vanced tumor grade and poor survival in vari- minal-to-basal transition scenario. The absence ous carcinomas including skin, head and neck, of ILC formation in the aforementioned studies prostate, lung, gastric, and breast (Tada et al. might be caused by the oncogene-driven back- 2000; Klus et al. 2001; Winn et al. 2002; Shiina ground, because loss of E-cadherin in the et al. 2005; Andreu et al. 2006; Akai et al. 2006). MMTV-PyMTand MMTV-ErbB2 mouse mod- In line with these findings is the recent observa- els also does not lead to ILC (R. Kemler, pers. tion that DSG3 controls E-cadherin membrane comm.). In conclusion, it appears that overex- trafficking (Moftah et al. 2016). Loss of desmo- pression of growth factor receptors or oncogen- somal proteins may be induced through epige- ic RAS/RAF/SRC signals do not provide the netic mechanisms (Oshiro et al. 2005), suggest- cues that underpin the typical E-cadherin ing that the mode of inactivation may reflect loss-type tumors, such as HDGC and ILC. In timing of the event, as is the case for E-cadherin. contrast, specific aberrations in PI3K signals Although there is currently little information (Annunziato et al. 2016) or p53 loss (Derksen regarding mutational inactivation of DS genes et al. 2006; Shimada et al. 2012) seem to provide in human cancer, functional inactivation of the the correct instigating hit to allow for E-cad- DS may predispose to invasiveness. An example herin loss thus driving carcinoma development for this hypothesis is the finding that condition- and progression that is typical for early E-cad- al inactivation of (DSP) in the herin inactivation. Rip1Tag2 mouse model of pancreatic cancer re- The architecture of the (DS) sulted in increased local invasion of E-cadherin resembles that of the AJ in that they are also expressing tumor cells (Chun and Hanahan comprised of cadherins and armadillo-type 2010), thus advocating the possibility that des- proteins that connect the DS to the underlying mosomal inactivation may also precede late AJ intermediate filaments. (DSG) inactivation in IDC and thereby promote tumor and (DSC) are nonclassical cad- progression. herins that mediate adhesion through interac- In conclusion, direct genetic inactivation of tions of their ectodomains. Linkage with the AJ components that are directly linked to actin intermediate filament cytoskeleton is controlled remodeling is causal to tumor development and by (aka g-catenin or JUP) and the progression in ILC and HDGC, whereas late (PKP) that interact with the IF inactivation may control metastatic behavior binding protein desmoplakin (reviewed by in other tumor types like IDC. Likewise, inacti- Delva et al. 2009). Interestingly, plakoglobin is vation of DS and TJ function is frequently ob- highly similar to, and can in part functionally served, although the cause for inactivation replace, b-catenin (McCrea et al. 1991; Butz remains elusive and their contribution to et al. 1992), whereas PKP4 (p0071) is a p120 E-cadherin negative ILC harboring wild-type family member (Hatzfeld and Nachtsheim CDH1 alleles is unknown. Given that integrity 1996), exemplifying the substantial similarity and function of epithelial adhesion complexes of the two junctional complexes. Like the AJ- heavily depend on their associated and neigh- related catenins, DS components have been boring complex members, it will be interesting associated with tumor suppressor as well as on- to map and functionally validate inactivating

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mutations of AJ-associated complexes such as strongly linked to YAP-induced proliferation the TJ and DS to establish whether they contrib- through TEAD-dependent transcription (Wada ute to the cancers that are driven by E-cadherin et al. 2011; Aragona et al. 2013). Support for the loss of function. assumption that loss of E-cadherin is associated with acquisition of YAPactivity are findings that YAP controls cancer progression (Lamar et al. BIOCHEMICAL CONSEQUENCES OF EARLY 2012; Chen et al. 2012) and that, IDC, ILC, and E-CADHERIN LOSS IN CANCER its precursor lesion, LCIS are characterized by nu- In the last decade a number of studies have ad- clear YAP localization (Vlug et al. 2013b and dressed the biochemical and functional conse- E. Vlug, unpubl.). Interestingly, in the normal quences of mutational E-cadherin inactivation mammary gland only myoepithelial cells express in cancer. These studies showed that, despite the nuclear YAP(Vlug et al. 2013b; Jaramillo-Rodri- assumption by many that b-catenin would be guez et al. 2014), suggesting that luminal ILC uncoupled from the AJ on mutational inactiva- cells have obtained a distinct basal cellular fea- tion of E-cadherin and subsequently contribute ture that might enhance tumor progression. to canonical WNTsignaling, this was shown not In parallel, nuclear localization of p120 is to be the case. Instead, it has become evident that increased approximately two-fold in anchor- E-cadherin inactivating mutations in cancer age-independent ILC cells, which leads to tran- cells lead to low b-catenin expression without scriptional derepression of the Kaiso target gene an increase in nuclear translocation and subse- Wnt11 to drive autocrine Rho-Rock activity (van quent induction of TCF/LEF-dependent tran- de Ven et al. 2015). This mechanism is essential scriptional activity (van de Wetering et al. 2001; to promote anoikis resistance of ILC cells (see Herzig et al. 2007; Schackmann et al. 2011). Un- Fig. 2). Interestingly, nuclear p120 acts as a rate like b-catenin, p120 is not degraded in human limiting inhibitor of Kaiso in transcriptionally ILC, but instead accumulates in the cytoplasm active regions, implying that Kaiso functions as and nucleus. Several lines of evidence have im- a tumor suppressor in E-cadherin mutant cancer plicated an oncogenic function for p120. It has (van de Ven et al. 2015). Recently, a similar been well established that loss of E-cadherin mechanism was proposed in the p120-depen- leads to cytosolic translocation of p120 in a va- dent regulation of REST/CoREST-mediated riety of different tumor types including breast, transcriptional repression of genes involved in colon, lung, and gastric tumors (Thoreson and stem cell differentiation (Lee et al. 2014). Togeth- Reynolds 2002). Studies in breast and colon can- er, they suggest that nuclear p120 may have a cer indicate that cytosolic expression of p120 broad function in the regulation of transcrip- controls the invasive phenotype of E-cadherin tional derepression on E-cadherin loss in cancer. negative cells (Bellovin 2005; Macpherson et al. In more basal-type breast cancers where E- 2007; Soto et al. 2008; Schackmann et al. 2011). cadherin is inactivated through epigenetic In mouse and human ILC models, p120 trans- mechanisms, p120 is also translocated to the locates to the cytosol where it drives anchorage- cytosol. In contrast to ILC however, MDA- independent survival and metastatic dissemina- MB-231 cells (a triple negative and Claudin tion (Schackmann et al. 2011). Mechanistically, low IDC cell line) showed p120 binding to mes- p120 controls anoikis resistance of E-cadherin enchymal cadherins such as Cadherin-11, mutant cells by indirect activation of Rho-asso- which controlled activation of Rac1 and Ras- ciated kinase 1 (Rock1) through binding and MAPK signaling (Yanagisawa and Anastasiadis inhibition of Rho antagonist myosin phospha- 2006; Soto et al. 2008). Similar findings have tase Rho-interacting Protein (MRIP) (Schack- been obtained in Ras or Src-transformed mann et al. 2011) (see Fig. 2). In conjunction MDCK cells (Dohn et al. 2009). These findings with the Rock-mediated effects, E-cadherin loss appear counterintuitive and might be cell-type might also induce YAP/TAZ signals because specific, because Cadherin-11 is usually not lo- Rock-mediated actomyosin contraction is calized the cytosolic compartment of the cell

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(Pishvaian et al. 1999). However, regardless of pendent anchorage-independent tumor growth the cell type used, a common denominator in and metastasis (reviewed in Christgen and these studies was the acquisition of invasiveness Derksen 2015). Rock1 regulates the actomyo- and anchorage-independent growth. Given sin-dependent contraction of the actin cytoskel- these characteristics, disseminating ILC cells eton and cellular metabolism through phos- may have developed autocrine biochemical phorylation of downstream effectors such as cues that promote cellular survival ex situ, an Cofilin (Maekawa et al. 1999) and Myosin Light assumption that is in line with the observations Chain (MLC) (Totsukawa et al. 2000). In cancer, that cytosolic and nuclear translocation of p120 activation or overexpression of Rho GTPases can drive distinct transcriptional programs and downstream Rock signaling components (Kim et al. 2004; Lee et al. 2014). Based on the correlate strongly with invasion, angiogenesis virtual absence of a canonical WNT signal in E- and overall aggressiveness of several tumors (Sa- cadherin mutant cancer cells and the overlap hai and Marshall 2002). In vitro studies and between Kaiso and TCF/LEF targets (Park animal models have suggested that inhibition et al. 2005), the biological responses through of the Rho-Rock pathway may be a clinically p120/Kaiso- and b-catenin/TCF-dependent relevant target in cancer. In a rat hepatoma transcriptional activity may be mutually exclu- model, genetic experiments showed that kinase sive. As a consequence, specificity may have inhibition of Rock reduces tumor cell invasive- evolved to control homeostasis through differ- ness (Itoh et al. 1999). Furthermore, invasive- ential regulation of a given gene in response to ness of many cell lines can be decreased through distinct proximal signals. the Rock inhibitors Y-27632 (Itoh et al. 1999; In conclusion, the net effect of translocated Wicki and Niggli 2001) and WF-536 (Nakajima p120 in E-cadherin mutant cancer is the induc- et al. 2003). Preclinical usage of the clinically tion of anchorage-independence and migration approved antivasoconstrictive drug Fasudil in through several mechanisms: first, it activates mouse xenografting models of lung and breast actomyosin contraction through indirect acti- cancer specifically inhibited invasiveness and vation of Rock1; second, it binds and derepress- metastasis, rather than cellular proliferation es Kaiso to drive expression of distinct target (Ying et al. 2006). In conclusion, pharmacolog- genes like Wnt11 expression and subsequent ical inhibition of Rock signaling can inhibit autocrine RhoA activation; third, p120 controls prometastatic traits in a cell-type specific man- Kaiso-independent transcriptional processes ner and represents a prime candidate for clinical that may be beneficial for cancer progression implementation to inhibit HDGC and ILC. (see Fig. 2B for an overview of the affected path- Despite the striking phenotypical and func- ways). Based on the current literature, it appears tional similarities between the current mouse that in E-cadherin negative cancers that are not and human ILC models, a clinical characteristic caused by early mutational E-cadherin inactiva- of most ILC cases is the expression of the estro- tion, p120 is also retained in the cytosol, but gen receptor (ER) and accompanying respon- might control different tumor-promoting siveness to ER antagonists such as tamoxifen mechanisms caused by binding of mesenchy- and aromatase inhibitors (Sikora et al. 2013). mal-type cadherins (Yanagisawa and Anastasia- Unfortunately, neither the human ILC cell line dis 2006; Soto et al. 2008; Dohn et al. 2009). IPH-926 nor the mouse model systems express ER and are as such not satisfactory models for ER-positive ILC. Nonetheless, it is clear that ILC CLINICAL INTERVENTION OPTIONS AND patients in general cannot successfully be treat- FUTURE PERSPECTIVES ed using standard chemotherapy (Cristofanilli Studies in human and mouse ILC have shown et al. 2005; Purushotham et al. 2010), resulting that E-cadherin inactivation leads to multidrug in a poor overall prognosis if endocrine treat- resistance, up-regulation of BCL2, and auto- ment is unsuccessful. Given that the mouse and crine Wnt11-mediated activation of Rock-de- human ILC models are equally chemo-refractory

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H.C. Bruner and P.W.B. Derksen

to taxanes, platinum drugs and anthracyclines the in situ stages of breast cancer, resulting in (J. Jonkers and P. Derksen, unpubl.), and the filling of the mammary duct with anoikis-resis- fact that their etiology is based on E-cadherin- tant cells. This process can be triggered by acti- dependent AJ function, they are valuable tools vation of oncogenic growth factor receptor in identifying the downstream oncogenic effec- (GFR) signaling (Humphreys et al. 1996; Mu- tors that are unleashed on early E-cadherin loss. thuswamy et al. 2001; Schmelzle et al. 2007). A key feature of E-cadherin mutant cancer Because similar effects are triggered on inhibi- cells is that they can survive under anchorage- tion of BIM, BMF, and p53 (Schmelzle et al. independent conditions, a feature designated as 2007; Mailleux et al. 2007; Danes et al. 2008), anoikis resistance (Meredith et al. 1993; Frisch this indicates that either GFR activation and/ and Francis 1994). E-cadherin is causal in the or the inhibition of distal proapoptotic effectors acquisition of anchorage-independence be- underlie anchorage independence of breast cause re-expression of E-cadherin in E-cadherin cancer cells. Corroborating this is the fact that mutant cells leads to restoration of anoikis mutations in PI3K are common in breast cancer (Derksen et al. 2006). Interestingly, the litera- (Desmedt et al. 2016; Fang et al. 2016) and that ture has reported several ILC cases in which hyperactivation of PI3K and its downstream distant metastasis had developed without the effector AKT/PKB can lead to anoikis resistance presence of a detectable primary tumor mass through phosphorylation-dependent inactiva- (Engelstaedter and Mylonas 2011; Tomizawa tion of proapoptotic proteins like BAD and et al. 2012), a phenotype that was also observed BIM (Datta et al. 1997; Schmelzle et al. 2007). in the WAPcre-driven mouse models of human Interestingly, E-cadherin homotypic adhesion ILC (Derksen et al. 2011). Moreover, women inhibits GFR signaling (Qian et al. 2004) possi- suffering from ILC show a higher incidence in bly through an NF2/Merlin dependent intracel- the development of clonally-related contralater- lular mechanism (Curto et al. 2007). Because al lesions (Newstead et al. 1992). Together, these Merlin can form a complex with E-cadherin to data demonstrate that anoikis resistance is an stabilize the AJ-actin association (Sainio et al. intrinsic and cardinal feature of E-cadherin 1997; James et al. 2001; Curto et al. 2007), loss mutant cancers that provides the survival cue of E-cadherin may result in phosphorylation that controls anchorage independence during and unfolding of the closed Merlin configura- tumor cell dissemination. tion leading to decreased contact inhibition What prevents E-cadherin mutant cells caused by increased GFR (Cole et al. 2008), from undergoing anoikis? Mammary gland ho- Rac (Shaw et al. 2001), and YAP/TAZ signals meostasis depends on controlled spatiotempo- (Jahanshahi et al. 2016) (reviewed in Petrilli ral induction of anoikis in specific luminal ep- and Ferna´ndez-Valle 2016)(see Fig. 2B). ithelial cells that line the ductal structures, thus Alternatively, cadherins might repress GFR ensuring the formation of a hollow lumen activation through direct binding to neighbor- (Humphreys et al. 1996; Debnath et al. 2002; ing growth factor receptors such as EGFR (Qian Inman et al. 2015). In this homeostatic process, et al. 2004) or extracellular steric hindrance of the BH3-only proapoptotic proteins BIM and growth factor presentation by heparin sulfate BMF induce anoikis resulting in clearance of the proteoglycans, an established mode of GFR at- central duct and subsequent formation of a tu- tenuation in cancer (Derksen et al. 2004). Final- bular structure (Mailleux et al. 2007; Schmelzle ly, AJs through regulation of TJs maintain a et al. 2007). Although proapoptotic protein ex- physical barrier, which could prevent growth pression can be induced by multiple stimuli, factor receptors from reaching their ligands be- including DNA damage, nutrient deprivation, cause of their difference in apical and basolat- heat and hypoxia (Strasser et al. 2011), BMF eral membrane localization (Mellman and Nel- seems to preferentially induce anoikis in epithe- son 2008). In cancer, experimental evidence for lial cells (Schmelzle et al. 2007; Hausmann et al. cadherin-dependent GFR repression was indi- 2011). Proper anoikis control is lost early during rectly provided by showing that AJ dismantling

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on p120 knockout led to anchorage-indepen- clinical usage is currently limited to lymphoid dent tumor growth and metastasis caused by malignancies, the BH3-only mimetics hold hypersensitization of endogenous GFR signal- promise as an alternative or complementary ing (Schackmann et al. 2013). Moreover, in treatment to specifically kill disseminating E- HDGC there is a correlation between increased cadherin mutant cancer cells. EGFR activation and the presence of mutant E- cadherin (Bremm et al. 2008). In line with these CONCLUDING REMARKS findings it was recently shown that E-cadherin mutant cells specifically fail to transcriptionally Early mutational somatic or germline inactiva- up-regulate BMF because of AKT-dependent tion of E-cadherin leads to the development and repression of FOXO3 (Hornsveld et al. 2016). progression of distinct cancer types in the breast Since extensive work by the Brugge laboratory and/or stomach. In the absence of functional has established that BIM may play similar roles redundancy by other classical cadherins, this in breast cancer through and GFR sig- results in loss of cell–cell adhesion and anchor- naling-dependent cues (Reginato et al. 2003), it age-independence, features that underpin the appears that aberrant control of the proapop- classical and typical invasive growth and cellular totic BH3-only proteins is a key distal event in phenotype of the resulting HDGC and ILC tu- E-cadherin mutant cancer. As such, it might mor types. Based on the available evidence, it represent a clinical Achilles heel in the manage- appears that early E-cadherin loss induces acti- ment of metastatic (H)DGC and ILC. Support- vation of two distinct oncogenic signals; first ing this reasoning is the finding that preclinical and foremost, constitutive Rock-dependent ac- treatment using BH3-only mimetics combined tomyosin activation and subsequent anchorage with chemotherapy or endocrine treatment reg- independence is induced by cytosolic p120; sec- imens could successfully inhibit ER-positive ond, E-cadherin loss leads to hypersensitization breast cancer (Oakes et al. 2012; Vaillant et al. of GFR signals, which attenuates FOXO-depen- 2013). dent transcriptional repression of the key pro- This wealth of experimental data may have apoptotic players BMF and BIM (see Fig. 3). In important clinical ramifications through the use addition, distinct transcriptional programs that of -based or small molecule regimens might underlie E-cadherin deficient tumor eti- that specifically inhibit GFR signaling, especial- ology are instigated by transcriptional p120/ ly because hyperactivation of GFR signals in E- Kaiso derepression, activation of YAP/TAZ cadherin mutant cells appears to be instigated and probably other, currently unidentified tran- independent of somatic mutations that activate scriptional programs. PI3K/AKT signals (M. Tenhagen, unpubl.). Because loss of the actin linker a-catenin However, it appears that using proximal inhibi- can, in principle, also initiate a classical E-cad- tion of GFR (e.g., targeting the ErbB1/2 recep- herin-deficient cancer phenotype (in contrast tors) in cancer is not the preferable strategy, to loss of p120) and most evidence points to- because this treatment option is plagued by tu- ward activation of actomyosin contraction by mor relapses caused by unsuccessful debulking Rho/Rock, YAP/TAZ, and NF2/Merlin, we (tumor cell ablation through chemo or targeted propose that E-cadherin mutant cancers like anticancer therapies) and subsequent selection HDGC and ILC should be considered “actin” of resistant clones (Diaz et al. 2012; Gagliato diseases. We think this term covers the essence et al. 2016). For cancers driven by E-cadherin of these diseases because they are primarily loss, the preferable intervention strategy would driven by linkage loss between the AJ and the then be to either focus on inhibitors of the more actin cytoskeleton and a subsequent propaga- downstream AKT hub and combine them with tion of, and dependency on, constitutive acto- activation of the most distal antitumor event or myosin contractility. Moreover, the identifica- the induction of apoptosis through inhibition tion of inactivating CTNNA1 mutations in of proapoptotic BCL molecules. Although their HDGC or ILC patients suggests that, in princi-

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dependent actomyosin contraction acts in GF parallel to or operates in conjunction with Wnt11 GFR-dependent activation of PI3K/AKT and GFR the repression of BIM/BMF. Notwithstanding this we feel that from a clinical point of view the current scientific evidence paves the P P way for targeted intervention of cancers like HDGC and ILC using inhibitors of Rock, AKT, and BCL2 (the BH3-only mimetics), PI3K alone or in combination with standard endo- RhoA 2 Akt p120 crine or chemotherapy regimens (see Fig. 3 for an overview). Mrip

Rock FOXO3 ACKNOWLEDGMENTS 1 BMF We would like to thank Dana Pirone and Johan F-actin BCL2 de Rooij for critically reading this manuscript. 3 The Derksen and van Diest laboratories are ac- knowledged for support and suggestions. This Tumor progression Research was supported by grants from the Netherlands Organization for Scientific Re- Figure 3. Options for clinical intervention of cancers search (NWO/ZonMW-VIDI 016.096.318), driven by early E-cadherin loss. ILC tumor growth Foundation Vrienden UMC Utrecht (11.081), and metastasis are driven by p120-dependent activa- the Dutch Cancer Society (KWF-UU-2011- tion of Rock and hyperactivation of GFR signaling on 5230, KWF-UU-2014-7201, and KWF-UU- E-cadherin inactivation (as outlined in Fig. 2B). As a result, PI3K/AKT signals will inhibit FOXO3-medi- 2016-10456) and H2020-FETPROACT/2016- ated BMF transcription and prevent programmed cell 2017/731957. death in the absence of anchorage. Clinical interven- tion should therefore focus on inhibition of Rock, PI3K/AKT, and BCL2 using BH3-only mimetics. REFERENCES Combining these targeted treatments with standard chemotherapy and/or endocrine drugs to inhibited Agiostratidou G, Li M, Suyama K, Badano I, Keren R, Chung estrogen receptor (ER) function, might be beneficial S, Anzovino A, Hulit J, Qian B, Bouzahzah B, et al. 2009. in cancers driven by early E-cadherin loss, such as Loss of retinal cadherin facilitates mammary tumor pro- (hereditary) diffuse gastric cancer (HDGC) and in- gression and metastasis. Cancer Res 69: 5030–5038. vasive lobular breast cancer (ILC). Akai T, Nabeya Y, Yahiro K, Morinaga N, Mitsuhashi K, Inoue M, Sakamoto A, Ochiai T, Noda M. 2006. Helico- bacter pylori induces mono-(adenosine 5’-diphosphate)- ribosylation in human gastric adenocarcinoma. Int J On- pal, any mutation that functionally results in col 29: 965–972. an “E-cadherin-type” actin deregulation, might Albergaria A, Ribeiro AS, Vieira A-F, Sousa B, Nobre A-R, Seruca R, Schmitt F, Paredes J. 2011. P-cadherin role in underpin the development of these cancers. In normal breast development and cancer. Int J Dev Biol 55: line with this rationale we hypothesize that 811–822. (similar to E-cadherin or a-catenin loss), aber- Andreu P,Colnot S, Godard C, Laurent-Puig P,Lamarque D, Kahn A, Perret C, Romagnolo B. 2006. Identification of rant control or loss of distinct desmosomal or the IFITM family as a new molecular marker in human TJ molecules at the initiating stages of cancer colorectal tumors. Cancer Res 66: 1949–1955. development might cause deregulation of AJ- Annunziato S, Kas SM, Nethe M, Yu¨cel H, Del Bravo J, dependent cell–cell adhesion and actomyosin Pritchard C, Bin Ali R, van Gerwen B, Siteur B, Drenth AP,et al. 2016. Modeling invasive lobular breast carcino- contraction, leading to HDGC or ILC. It is ma by CRISPR/Cas9-mediated somatic genome editing currently unclear whether activation of Rock- of the mammary gland. Genes Dev 30: 1470–1480.

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Loss of E-Cadherin-Dependent Cell−Cell Adhesion and the Development and Progression of Cancer

Heather C. Bruner and Patrick W.B. Derksen

Cold Spring Harb Perspect Biol 2018; doi: 10.1101/cshperspect.a029330 originally published online May 15, 2017

Subject Collection Cell-Cell Junctions

Vascular Endothelial (VE)-Cadherin, Endothelial Signaling by Small GTPases at Cell−Cell Adherens Junctions, and Vascular Disease Junctions: Protein Interactions Building Control Maria Grazia Lampugnani, Elisabetta Dejana and and Networks Costanza Giampietro Vania Braga Adherens Junctions and Desmosomes Making Connections: Guidance Cues and Coordinate Mechanics and Signaling to Receptors at Nonneural Cell−Cell Junctions Orchestrate Tissue Morphogenesis and Function: Ian V. Beamish, Lindsay Hinck and Timothy E. An Evolutionary Perspective Kennedy Matthias Rübsam, Joshua A. Broussard, Sara A. Wickström, et al. Cell−Cell Contact and Receptor Tyrosine Kinase The Cadherin Superfamily in Neural Circuit Signaling Assembly Christine Chiasson-MacKenzie and Andrea I. James D. Jontes McClatchey Hold Me, but Not Too Tight−−Endothelial Cell−Cell Mechanosensing and Mechanotransduction at Junctions in Angiogenesis Cell−Cell Junctions Anna Szymborska and Holger Gerhardt Alpha S. Yap, Kinga Duszyc and Virgile Viasnoff and Disease Beyond Cell−Cell Adhesion: Sensational Mario Delmar, Dale W. Laird, Christian C. Naus, et Cadherins for Hearing and Balance al. Avinash Jaiganesh, Yoshie Narui, Raul Araya-Secchi, et al. Cell Junctions in Hippo Signaling Cell−Cell Junctions Organize Structural and Ruchan Karaman and Georg Halder Signaling Networks Miguel A. Garcia, W. James Nelson and Natalie Chavez

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Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved Downloaded from http://cshperspectives.cshlp.org/ on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press

Loss of E-Cadherin-Dependent Cell−Cell Adhesion Cell Biology of Tight Junction Barrier Regulation and the Development and Progression of Cancer and Mucosal Disease Heather C. Bruner and Patrick W.B. Derksen Aaron Buckley and Jerrold R. Turner Desmosomes and Intermediate Filaments: Their Integration of Cadherin Adhesion and Consequences for Tissue Mechanics Cytoskeleton at Adherens Junctions Mechthild Hatzfeld, René Keil and Thomas M. René Marc Mège and Noboru Ishiyama Magin

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Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved