Breast tumor heterogeneity has been well documented through the use of multiplatform –omic studies in human tumors. However, there is no integrative database to capture the heterogeneity within mouse models of breast cancer. This project identifies genomic copy number alterations (CNAs) in 600 tumors across 27 major mouse models of breast cancer through the application of a predictive algorithm to publicly available gene expression data. It was found that despite the presence of strong oncogenic drivers in most mouse models, CNAs are extremely common but heterogeneous both between models and within models. Many mouse CNA events are largely conserved in human tumors and in the mouse we show that they are associated with secondary tumor characteristics such as tumor histology, metastasis, as well as enhanced oncogenic signaling. These data serve as an important resource in guiding investigators when choosing a mouse model to understand the gene copy number changes relevant to human breast cancer.
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Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707–12.
Escot C, Theillet C, Lidereau R, Spyratos F, Champeme MH, Gest J, et al. Genetic alteration of the c-myc protooncogene (MYC) in human primary breast carcinomas. Proc Natl Acad Sci U S A. 1986;83(13):4834–8.
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275(5308):1943–7.
Deming SL, Nass SJ, Dickson RB, Trock BJ. C-myc amplification in breast cancer: a meta-analysis of its occurrence and prognostic relevance. Br J Cancer. 2000;83(12):1688–95.
Menard S, Fortis S, Castiglioni F, Agresti R, Balsari A. HER2 as a prognostic factor in breast cancer. Oncology. 2001;61(Suppl 2):67–72.
Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990;250(4988):1684–9.
Feilotter HE, Coulon V, McVeigh JL, Boag AH, Dorion-Bonnet F, Duboue B, et al. Analysis of the 10q23 chromosomal region and the PTEN gene in human sporadic breast carcinoma. Br J Cancer. 1999;79(5–6):718–23.
Shimada H, Stram DO, Chatten J, Joshi VV, Hachitanda Y, Brodeur GM, et al. Identification of subsets of neuroblastomas by combined histopathologic and N-myc analysis. J Natl Cancer Inst. 1995;87(19):1470–6.
Wang S, Gao J, Lei Q, Rozengurt N, Pritchard C, Jiao J, et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell. 2003;4(3):209–21.
Fujita T, Doihara H, Kawasaki K, Takabatake D, Takahashi H, Washio K, et al. PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer. Br J Cancer. 2006;94(2):247–52.
Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20(3):719–26.
Network TCGA. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70.
Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486(7403):346–52.
Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98(19):10869–74.
Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 2010;12(5):R68.
Muller WJ, Sinn E, Pattengale PK, Wallace R, Leder P. Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell. 1988;54(1):105–15.
Sinn E, Muller W, Pattengale P, Tepler I, Wallace R, Leder P. Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell. 1987;49(4):465–75.
Stewart TA, Pattengale PK, Leder P. Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell. 1984;38(3):627–37.
Cardiff RD, Anver MR, Gusterson BA, Hennighausen L, Jensen RA, Merino MJ, et al. The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting. Oncogene. 2000;19(8):968–88.
Andrechek ER, Hardy WR, Siegel PM, Rudnicki MA, Cardiff RD, Muller WJ. Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis. Proc Natl Acad Sci U S A. 2000;97(7):3444–9.
McCarthy A, Savage K, Gabriel A, Naceur C, Reis-Filho JS, Ashworth A. A mouse model of basal-like breast carcinoma with metaplastic elements. J Pathol. 2007;211(4):389–98.
Xu X, Wagner KU, Larson D, Weaver Z, Li C, Ried T, et al. Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nat Genet. 1999;22(1):37–43.
D'Cruz CM, Gunther EJ, Boxer RB, Hartman JL, Sintasath L, Moody SE, et al. C-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations. Nat Med. 2001;7(2):235–9.
Moody SE, Sarkisian CJ, Hahn KT, Gunther EJ, Pickup S, Dugan KD, et al. Conditional activation of neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis. Cancer Cell. 2002;2(6):451–61.
Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ. Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci U S A. 1992;89(22):10578–82.
Herschkowitz JI, Zhao W, Zhang M, Usary J, Murrow G, Edwards D, et al. Comparative oncogenomics identifies breast tumors enriched in functional tumor-initiating cells. Proc Natl Acad Sci U S A. 2012;109(8):2778–83.
DeRose YS, Wang G, Lin YC, Bernard PS, Buys SS, Ebbert MT, et al. Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Nat Med. 2011;17(11):1514–20.
Hollern DP, Andrechek E. A genomic analysis of mouse models of breast cancer reveals molecular features of mouse models and relationships to human breast cancer. Breast Cancer Res. 2014, 16(R59).
Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, et al. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol. 2007;8(5):R76.
Pfefferle AD, Herschkowitz JI, Usary J, Harrell JC, Spike BT, Adams JR, et al. Transcriptomic classification of genetically engineered mouse models of breast cancer identifies human subtype counterparts. Genome Biol. 2013;14(11):R125.
Silva GO, He X, Parker JS, Gatza ML, Carey LA, Hou JP, et al. Cross-species DNA copy number analyses identifies multiple 1q21-q23 subtype-specific driver genes for breast cancer. Breast Cancer Res Treat. 2015;152(2):347–56.
Hu G, Chong RA, Yang Q, Wei Y, Blanco MA, Li F, et al. MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer. Cancer Cell. 2009;15(1):9–20.
Ciriello G, Gatza ML, Beck AH, Wilkerson MD, Rhie SK, Pastore A, et al. Comprehensive molecular portraits of invasive lobular breast cancer. Cell. 2015;163(2):506–19.
Hodgson JG, Malek T, Bornstein S, Hariono S, Ginzinger DG, Muller WJ, et al. Copy number aberrations in mouse breast tumors reveal loci and genes important in tumorigenic receptor tyrosine kinase signaling. Cancer Res. 2005;65(21):9695–704.
Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121(7):2750–67.
Helmrich A, Stout-Weider K, Hermann K, Schrock E, Heiden T. Common fragile sites are conserved features of human and mouse chromosomes and relate to large active genes. Genome Res. 2006;16(10):1222–30.
Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, et al. Genes that mediate breast cancer metastasis to lung. Nature. 2005;436(7050):518–24.
Bild AH, Yao G, Chang JT, Wang Q, Potti A, Chasse D, et al. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature. 2006;439(7074):353–7.
Gatza ML, Lucas JE, Barry WT, Kim JW, Wang Q, Crawford MD, et al. A pathway-based classification of human breast cancer. Proc Natl Acad Sci U S A. 2010;107(15):6994–9.
Ben-David U, Ha G, Khadka P, Jin X, Wong B, Franke L, et al. The landscape of chromosomal aberrations in breast cancer mouse models reveals driver-specific routes to tumorigenesis. Nat Commun. 2016;7:12160.
Andrechek ER, Cardiff RD, Chang JT, Gatza ML, Acharya CR, Potti A, et al. Genetic heterogeneity of myc-induced mammary tumors reflecting diverse phenotypes including metastatic potential. Proc Natl Acad Sci U S A. 2009;106(38):16387–92.
Boxer RB, Jang JW, Sintasath L, Chodosh LA. Lack of sustained regression of c-MYC-induced mammary adenocarcinomas following brief or prolonged MYC inactivation. Cancer Cell. 2004;6(6):577–86.
Siegel PM, Ryan ED, Cardiff RD, Muller WJ. Elevated expression of activated forms of neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer. EMBO J. 1999;18(8):2149–64.
Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010;123(3):725–31.
Andrechek ER. HER2/neu tumorigenesis and metastasis is regulated by E2F activator transcription factors. Oncogene. 2015;34(2):217–25.
Fujiwara K, Yuwanita I, Hollern DP, Andrechek ER. Prediction and genetic demonstration of a role for activator E2Fs in myc-induced tumors. Cancer Res. 2011;71(5):1924–32.
Yuwanita I, Barnes D, Monterey MD, O'Reilly S, Andrechek ER. Increased metastasis with loss of E2F2 in myc-driven tumors. Oncotarget. 2015;6(35):38210–24.
Hollern DP, Honeysett J, Cardiff RD, Andrechek ER. The E2F transcription factors regulate tumor development and metastasis in a mouse model of metastatic breast cancer. Mol Cell Biol. 2014;34(17):3229–43.
Andrechek ER, Mori S, Rempel RE, Chang JT, Nevins JR. Patterns of cell signaling pathway activation that characterize mammary development. Development. 2008;135(14):2403–13.
West M, Blanchette C, Dressman H, Huang E, Ishida S, Spang R, et al. Predicting the clinical status of human breast cancer by using gene expression profiles. Proc Natl Acad Sci U S A. 2001;98(20):11462–7.
Szklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, Minguez P, et al. The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res. 2011;39(Database issue):D561–8.
We thank the members of the Andrechek laboratory for helpful discussions.
JR and EA collaborated on the study conception, design, and interpretation of results. BT provided histological coordination with CNA. HW provided the ACE analysis for many mouse models. JR performed all other experiments and drafted the manuscript. All authors have critically read, edited, and approved the final version of the manuscript.
Conflict of Interest
The authors declare they have no conflict of interest.
This work was supported with NIH R01CA160514 to E.R. A and 1F99CA212221–01 to J.R.
Electronic supplementary material
– Correlation between copy number alterations and gene expression data. The TGCA data was queried for copy number alterations and protein levels in EGFR (a) and FOXO3 (b). These samples were separated in to five categories, Deep deletion (homozygous deletion), Shallow deletion (heterozygous deletion), diploid, Gain (low level amplification), and amplification (high level amplification). A positive correlation between increased copy number and protein level was identified. (PDF 423 kb)
– Mouse genetic background and number of copy number alterations. To identify the effect of mouse strain on the stability of a mouse model we used mouse models with the same oncogenic driver on different mouse model backgrounds. This was done with the MMTV-PyMT (a), TAG (b), and p53/BRCA (c) models. It was found that in the PyMT model significantly more alterations were found in the FVB background (N = 66) when compared to the AKXD model (N = 55) (P < .01). A similar result was noted with the TAG model where the FVB background (N = 37) had significantly more alterations than TAG driven tumors in a Balb/C background (N = 3) (P < .05). In the BRCA/p53 models we found the C57 Bl/6 model (N = 12) to be more unstable compared to the Balb/C background (N = 73) (P < .01). (PDF 281 kb)
– Amplification or Deletion in specific mouse models. Heatmap representation of the data in Figure 2B. Containing amplification or deletion percentages in specific mouse models. Percentages are displayed as a value between 0 (blue) and 100% (red). The figure is split into amplifications (left) and deletions (right) (PDF 492 kb)
– Full heatmap associated with Figure 3A. (a) To assess the conservation of CNAs in mouse models and human patients unsupervised hierarchical complete linkage clustering of samples across human and mouse tumors were clustered by recurrent CNA events (N = 597) that were amplified or deleted in greater than 5% of mouse and human tumors. The dataset used the complete mouse models dataset of 27 mouse models (N = 600) and randomly chosen TCGA breast cancer tumors across all five major subtypes of breast cancer (N = 559). The clustering revealed three tight clusters composed of human and mouse samples as indicated by the purple, yellow, and green clusters. (PDF 451 kb)
- Role of CNA in oncogenic signaling pathways. (a) Spearman’s rank correlation of amplification (red) or deletion (blue) events with high activity of oncogenic signaling pathways is shown. Events are arranged by chromosomal location as indicated at the top for the pathways indicated at the right. The String-DB derived connectivity map of RB-E2F (B) networks is depicted. Rb and E2F2 are denoted by black arrows. All other colored nodes are genes which have a copy number alteration significantly correlated with a particular signaling pathway indicated by black circles, with the exception of Rb and E2F2. (PDF 1479 kb)
– Percent amplified or deleted at a particular genetic locus. Each locus identified by gene name, Affymetrix probe ID, as well as genomic location. Shows the percent amplified or deleted across the database and within each specific model. (XLSX 7459 kb)
– Conserved metastasis related CNAs. Conserved amplified or deleted genes that are associated with high lung metastasis score that are highly conserved across mouse and human breast cancer samples. This is a searchable table with the coordination of mouse and human data (TCGA dataset). Genes are split into those which perform the same in each species and those that are different. Genes are searchable by Gene symbol or mouse and human locations. This table also shows the KMplot data and metabric data to place each gene into context of gene expression and Distant Metastasis Free Survival and Overall Survival. (XLSX 557 kb)
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Rennhack, J., To, B., Wermuth, H. et al. Mouse Models of Breast Cancer Share Amplification and Deletion Events with Human Breast Cancer. J Mammary Gland Biol Neoplasia 22, 71–84 (2017). https://doi.org/10.1007/s10911-017-9374-y
- Copy number variation
- Mouse model
- Breast cancer
- Gene expression