Lobular Breast Cancer: Molecular Basis, Mouse and Cellular Models Matthias Christgen1* and Patrick WB Derksen2*

Christgen and Derksen Breast Cancer Research (2015) 17:16 DOI 10.1186/s13058-015-0517-z REVIEW Lobular breast cancer: molecular basis, mouse and cellular models Matthias Christgen1* and Patrick WB Derksen2* distinct entity (scirrhous spheroidal cell carcinoma) long Abstract before the terminus ILC became established [2]. Infiltrating lobular breast cancer (ILC) is the most In the 1980s, uvomorulin (E-cadherin) was discovered common special breast cancer subtype. With as a transmembrane glycoprotein that mediates cis and mutational or epigenetic inactivation of the cell trans calcium-dependent homotypic cell adhesion in adhesion molecule E-cadherin (CDH1) being confined epithelial tissues, thereby controlling cell polarity and almost exclusively to ILC, this tumor entity stands out proper blastocyst formation during embryogenesis [3]. from all other types of breast cancers. The molecular Together with the associated catenins, E-cadherin forms basis of ILC is linked to loss of E-cadherin, as evidenced the adherens junction (AJ) on the apical side of the cell, by human CDH1 germline mutations and conditional where it links the plasma membrane to the actin and knockout mouse models. A better understanding of ILC microtubule cytoskeleton [4]. E-cadherin is of pivotal beyond the level of descriptive studies depends on relevance for two special tumor entities, namely ILC and physiologically relevant and functional tools. This review diffuse gastric cancer (DGC). In the 1990s, it was reported provides a detailed overview on ILC models, including that nearly all ILCs and their adjacent intraepithelial well-characterized cell lines, xenograft tumors and precursor lesions, termed lobular carcinoma in situ genetically engineered mouse models. We consider (LCIS), lacked E-cadherin expression [5,6]. E-cadherin is advantages and limitations of these models and evaluate encoded by the CDH1 gene on chromosome 16q22. their representativeness for human ILC. The still Loss of E-cadherin in LCIS and ILC is due to somatic incompletely defined mechanisms by which loss of CDH1 frameshift mutation and loss of heterozygosity E-cadherin drives malignant transformation are discussed or aberrant CDH1 promoter methylation [7-9]. CDH1 based on recent findings in these models. Moreover, germline mutations are associated with the hereditary candidate genes and signaling pathways potentially DGC syndrome [10] and ILC belongs to the tumor involved in ILC development and progression as well as spectrum in these patients [11]. Cases of LCIS and anticancer drug and endocrine resistance are highlighted. ILC associated with CDH1 germline mutation without gastric cancer are also increasingly recognized [12]. In addition to genetically engineered mouse (GEM) Introduction models (see below), these findings from medical genetics Infiltrating lobular breast cancer (ILC) is the most have provided evidence that E-cadherin functions as a common special breast cancer (BC) subtype and accounts tumor suppressor and that its inactivation underpins for 10 to 15% of all mammary carcinomas. ILCs are ILC etiology. defined by histomorphological characteristics, such as The molecular impact of E-cadherin inactivation has small, discohesive and nonpolarized tumor cells with been studied extensively in the context of a biological little nuclear atypia and a single-file invasion pattern process referred to as the epithelial-to-mesenchymal (Figure 1A). Although first termed ILCs in the 1940s [1], transition. While these studies have provided vast insight these tumors had been recognized as a histologically into the epigenetic mechanisms that can silence E-cadherin and their functional consequences, they also indicated that E-cadherin inactivation through transcriptional repressors * Correspondence: [email protected]; [email protected] is not the main driver of ILC development. Based on 1Institute of Pathology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany immunohistochemical and genetic studies, it is now 2Department of Pathology, Utrecht University Medical Center, Heidelberglaan established that loss of E-cadherin triggers secondary 100, 3584 Utrecht, The Netherlands © 2015 Christgen and Derksen; licensee BioMed Central. The licensee has exclusive rights to distribute this article, in any medium, for 6 months following its publication. After this time, the article is available under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Christgen and Derksen Breast Cancer Research (2015) 17:16 Page 2 of 9 Figure 1 Infiltrating lobular breast cancer, a human infiltrating lobular breast cancer cell line and a genetically engineered mouse model for infiltrating lobular breast cancer. (A) Representative photomicrographs of infiltrating lobular breast cancer (ILC) stained with hematoxylin and eosin (left) or subjected to immunohistochemistry for E-cadherin (right). Note the E-cadherin-positive normal mammary gland duct surrounded by E-cadherin-negative ILC cells. (B) Molecular evolution of the IPH-926 ILC cell line. Photomicrographs show the histomorphology of the corresponding clinical tumor specimens and the IPH-926 cell line in vitro. Arrow highlights a single file linear cord reminiscent of primary ILC. AI, aromatase inhibitor; CTX, various conventional chemotherapies; LIR, local irradiation; TAM, tamoxifen; TSPP, transition to a secondary pleomorphic phenotype; yrs, years; M, mutational inactivation; ↑, overexpression; ↓, loss of expression. (C) Reconstitution of E-cadherin in ILC cells induces relocation of p120-catenin (p120) to the cell membrane. Shown are fluorescence images of IPH-926 cells transiently transfected with an E-cadherin–enhanced green fluorescent protein (Ecad-EGFP) expression construct and stained with an anti-p120-Alexa647 antibody. Closed arrow, cells with ectopic expression of Ecad-EGFP; open arrow, a cell without Ecad-EGFP. Note the accentuated membranous p120 staining in cells expressing Ecad-EGFP. DAPI, 4′,6-diamidino-2-phenylindole. (D) Mouse ILC from genetically engineered mouse models. Left, a tumor reminiscent of classic ILC; right, a pleomorphic mouse ILC. Both micrographs generated from the WAPcre;Cdh1F/F;Trp53F/F mouse ILC model. changes affecting several cadherin/catenin complex Review molecules. These changes include loss of β-catenin and Human ILC cell lines are a rare resource aberrant cytoplasmic and/or nuclear localization of Human BC cell lines are a powerful experimental tool. p120-catenin (p120) [13,14]. In many instances, information derived from in vitro Almost all ILCs are estrogen receptor (ER)-positive and models with BC cell lines has improved the understanding belong to the luminal or normal-like molecular subtype of cancer [23]. In other studies, potentially misleading [15]. Their proliferation is slow and mostly estrogen data have been generated because cell lines were not dependent [16]. Overexpression or amplification of the representative for the tumor type investigated. Numerous ERBB2 oncogene is rare, although somatic activating studies have aimed to (re)classify BC cell lines in terms of mutations have been reported [17]. In contrast, mutational their tumor origin and molecular properties. This revealed activation of the PIK3CA oncogene is a dominant a lack of ILC cell lines [23,24]. Among more than 100 BC feature in ILC [18]. TP53 mutations are rare [15], cell lines established to date, only seven can be tracked except for a more aggressive ILC variant termed back to histologically confirmed or suspected primary pleomorphic ILC, which is more often ER-negative and ILCs (Table 1) [25-31]. Importantly, an ILC origin cannot occasionally ERBB2-positive [19,20]. Based on these be concluded simply based on the lack of E-cadherin findings and various genomic profiling studies [15,21,22], expression. This is because in vitro culturing can induce it became evident that ILC represents a biologically epithelial-to-mesenchymal transition and a subsequent distinct entity. epigenetic silencing of E-cadherin [32]. In particular, A better understanding of ILC beyond the descriptive this applies to BC cell lines with a basal molecular level of genetic and histopathological studies depends on subtype that have most probably undergone epithelial-to- clinically relevant models. This review provides an overview mesenchymal transition in culture. A renowned example of mouse and human ILC models and their relevance for is MDA-MB-231. The MDA-MB-231 cell line lacks understanding ILC biology. E-cadherin due to hypermethylation, but is hardly Christgen and Derksen Breast Cancer Research (2015) 17:16 Page 3 of 9 Table 1 Human infiltrating lobular breast cancer cell models Protein expression Mutational status Molecular subtype Tumor origin Tissue Ecad ER PR ERBB2 CDH1 TP53 CTNNA1 References Cell lines MDA-MB-134 Unknown (ILC?) A Neg Pos Neg Neg muta wt/mutd wt lum [25,30,34-40,45] MDA-MB-330 ILC P Pos Neg Neg Pos wt mute muti ErbB2-pos [26,46] MA-11 Mixed ITC/ILC BM Pos Neg Neg Neg NA NA NA NA [27] SUM-44PE Unknown (ILC?) P Neg Pos Pos Neg mutb mutf wt lum [28,33,36-38] HCC-2185 ILC P NA Neg Neg Pos NA NA NA lum [24,29] IPH-926 ILC A Neg Neg Neg Neg mutc mutg

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