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Metastatic Canine Mammary Carcinomas Can Be Identified by A Klopfleisch et al. BMC Cancer 2010, 10:618 http://www.biomedcentral.com/1471-2407/10/618 RESEARCH ARTICLE Open Access Metastatic canine mammary carcinomas can be identified by a gene expression profile that partly overlaps with human breast cancer profiles Robert Klopfleisch1*, Dido Lenze2, Michael Hummel2, Achim D Gruber1 Abstract Background: Similar to human breast cancer mammary tumors of the female dog are commonly associated with a fatal outcome due to the development of distant metastases. However, the molecular defects leading to metastasis are largely unknown and the value of canine mammary carcinoma as a model for human breast cancer is unclear. In this study, we analyzed the gene expression signatures associated with mammary tumor metastasis and asked for parallels with the human equivalent. Methods: Messenger RNA expression profiles of twenty-seven lymph node metastasis positive or negative canine mammary carcinomas were established by microarray analysis. Differentially expressed genes were functionally characterized and associated with molecular pathways. The findings were also correlated with published data on human breast cancer. Results: Metastatic canine mammary carcinomas had 1,011 significantly differentially expressed genes when compared to non-metastatic carcinomas. Metastatic carcinomas had a significant up-regulation of genes associated with cell cycle regulation, matrix modulation, protein folding and proteasomal degradation whereas cell differentiation genes, growth factor pathway genes and regulators of actin organization were significantly down- regulated. Interestingly, 265 of the 1,011 differentially expressed canine genes are also related to human breast cancer and, vice versa, parts of a human prognostic gene signature were identified in the expression profiles of the metastatic canine tumors. Conclusions: Metastatic canine mammary carcinomas can be discriminated from non-metastatic carcinomas by their gene expression profiles. More than one third of the differentially expressed genes are also described of relevance for human breast cancer. Many of the differentially expressed genes are linked to functions and pathways which appear to be relevant for the induction and maintenance of metastatic progression and may represent new therapeutic targets. Furthermore, dogs are in some aspects suitable as a translational model for human breast tumors in order to identify prognostic molecular signatures and potential therapeutic targets. Background of CMT are usually followed by the development of dis- Canine mammary tumor (CMT) is the most common tant metastases, mainly in the lung, ultimately leading to cancer among female dogs and often becomes fatal due the death of the dog [6]. However, knowledge of the to the development of distant metastases [1-3]. Metasta- molecular mechanisms contributing to lymph node and sis to the regional lymph node is an early step in metas- distant metastasis is still fragmentary. Despite numerous tasis and one of the most important prognostic factors studies on this issue, significant metastasis-associated in the diagnosis of CMT, a criterion that is also valid and predictable expression patterns of single genes have for human breast cancer [4,5]. Lymph node metastases not been identified in CMT as yet [7-9]. Global gene expression profiles that compare metastasizing versus * Correspondence: [email protected] non-metastasizing CMT are unavailable whereas several 1 Department of Veterinary Pathology, Freie Universität Berlin, Robert-von- studies on human breast cancer found significant metas- Ostertag-Straße 15, 14163 Berlin, Germany Full list of author information is available at the end of the article tasis associated expression profiles. The latter studies © 2010 Klopfleisch et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Klopfleisch et al. BMC Cancer 2010, 10:618 Page 2 of 11 http://www.biomedcentral.com/1471-2407/10/618 identified several non-overlapping expression signatures The experimental research reported in the manuscript which are related to the development of lymph node has been performed with the approval of animal welfare and distant metastases and worse prognoses [10-13]. authorities and the ethical committee of the Freie Uni- The available studies on global gene expression in CMT versität Berlin. Surgical excision of tumour biopsies was compared normal mammary gland, benign and malig- part of the tumour treatment according to the state of nant tumors with unknown lymph node status and clini- the art treatment and solely to improve the animals wel- cal follow-up [14,15]. The authors reported that the fare. Furthermore, the animals were under full anaesthe- gene expression profiles of CMT include a gene expres- sia and not exposed to any additional manipulation due sion signature associated with neoplastic transformation. to the inclusion in this study. All animal owners Furthermore, comparison of canine and human expres- received and approved an informed client consent form. sion profiles disclosed an overlap of deregulated genes Tissue specimens were fixed in neutral-buffered 4% for- in human and canine mammary tumors [15]. Generally, malin or snap frozen in liquid nitrogen within 15 minutes clinical and molecular features of human and canine after resection and stored at -80°C until further use. For- bear a likeness in several aspects. Both malignancies are malin fixed tumor tissue samples were routinely the most common cancer of the female, lymph node embedded in paraffin and sections of 2-μmwerestained metastases indicate a poor prognosis, the hormonal sta- with hematoxylin and eosin. Tumor and lymph node tus influences the development of CMT and estrogen histologies were evaluated independently by two board- receptor (ER), progesterone receptor (PR) and ERBB2 certified pathologists, following the criteria of the WHO expression patterns do influence the overall survival rate classification of canine mammary tumors and the Notting- [1,16-18]. ham grading system [19,20]. All 27 tumors were simple The aim of this study was the identification of gene carcinomas and characterized by an invasive, mostly solid expression signatures in primary CMT that are asso- growth pattern, marked cellular pleomorphism, anisokar- ciated with early lymph node metastasis. Global mRNA yosis and 3 or more mitotic figures per high power field. expression profiles obtained from metastatic versus non- metastatic CMT cases were compared and differentially Immunohistochemistry expressed genes were analyzed for their function and Oestrogen receptor alpha (ER), ERBB2 expression was their role in pathway activation. Moreover, mining in immunohistochemically determined using the ABC- published literature revealed interesting overlapping fea- method. In brief, monoclonal mouse anti-human ER tures when compared to data derived from gene expres- specific antibody (1:1000, clone CC4-5, Novocastra, sion profiles of metastatic human breast carcinomas. Wetzlar, Germany) and rabbit polyclonal anti-human ERBB2 specific antibody (1:150, cat. no. A0485, Dako, Methods Hamburg, Germany) were diluted in Tris-buffered saline Tissue samples (TBS, 50 mM, pH 7.6) and incubated at 4°C overnight Thirteen simple mammary carcinomas with invasive after a blocking step with 50% goat serum in TBS for 30 growth and lymph node metastases at the time of tumor min at room temperature. Polyclonal goat anti-rabbit resection and 14 simple carcinomas without lymph node IgG (1:200; Vector, England, BA1000) and goat anti- metastases were included in the study (Table 1). Com- mouse IgG (1:200; BA9200, Vector, Burlingame, USA) plex carcinomas were excluded from the study to avoid were used as secondary antibody. Diaminobenzidine tet- differences in gene expression levels due to differences rahydrochloride (D8001, Sigma Aldrich, Munich, Ger- in mesenchymal/epithelial ratio in the different tissues. many) was used as chromogen and slides were None of the patients had a history of progestin treat- counterstained with hematoxylin (Merck). Normal ment or radiographically detectable pulmonary metas- canine and human mammary gland were used as posi- tases at the time of tumor resection. Distant metastases tive tissue controls. ER and ERBB2 immunolabeling was as the cause of death were determined postoperatively evaluated in 10 random 200× magnification fields. by radiographic detection of metastases (nos. 1-11) or Tumors were defined as ER or ERBB2 positive if more necropsy (nos. 12 and 13). Selection criteria for carcino- than 10% of the cells stained positive with the respective mas without lymph node metastases included an inva- antibody. sive growth, a negative lymph node status, a histological grade III and a minimal tumor diameter above the aver- Macrodissection of tumor samples and RNA isolation age of the lymph node positive tumors (> 2.42 cm). All Macrodissection was performed on all tumor specimens animals with non-metastatic carcinomas had a overall to ensure high tumor cellularity. Only sections with survival rate of over 24 months except animal no. 22 more than 70% carcinoma cells were included in the which developed radiographic detectable lung metas- study as shown by digital image analysis (Scanscope T3, tases 8 months after surgery.
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