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In Vivo Models in Breast Cancer Research: Progress, Challenges and Future Directions Ingunn Holen1, Valerie Speirs2, Bethny Morrissey2 and Karen Blyth3,*

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In Vivo Models in Breast Cancer Research: Progress, Challenges and Future Directions Ingunn Holen1, Valerie Speirs2, Bethny Morrissey2 and Karen Blyth3,* View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by White Rose Research Online © 2017. Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2017) 10, 359-371 doi:10.1242/dmm.028274 REVIEW In vivo models in breast cancer research: progress, challenges and future directions Ingunn Holen1, Valerie Speirs2, Bethny Morrissey2 and Karen Blyth3,* ABSTRACT receptor (ER), progesterone receptor (PR) and human epidermal Research using animal model systems has been instrumental in growth factor receptor-2 (HER2), and the main molecular subtypes delivering improved therapies for breast cancer, as well as in are termed Luminal A (ER/PR-positive); Luminal B (ER/PR- generating new insights into the mechanisms that underpin positive, higher histological grade than Luminal A); HER2- development of the disease. A large number of different models are positive; and triple-negative (ER/PR/HER2-negative) (Cardiff and now available, reflecting different types and stages of the disease; Kenney, 2011). Tailored therapies have led to considerable success choosing which one to use depends on the specific research question in treating some breast cancers, such as hormone therapies (e.g. (s) to be investigated. Based on presentations and discussions from tamoxifen, and inhibitors of the enzyme aromatase, involved in leading experts who attended a recent workshop focused on in vivo oestrogen synthesis) for ER-positive disease, and trastuzumab models of breast cancer, this article provides a perspective on the (Herceptin) for HER2-positive breast cancer; however, drug many varied uses of these models in breast cancer research, their resistance to these regimes is common (Osborne and Schiff, 2011; strengths, associated challenges and future directions. Among the Palmieri et al., 2014; Luque-Cabal et al., 2016). Furthermore, there questions discussed were: how well do models represent the different is still no good targeted therapy for triple-negative breast cancer, stages of human disease; how can we model the involvement of the which is one of the more aggressive subtypes of the disease human immune system and microenvironment in breast cancer; what (Kalimutho et al., 2015; Gu et al., 2016). In addition, whilst primary are the appropriate models of metastatic disease; can we use models breast cancer is highly treatable [80-99% of women diagnosed with to carry out preclinical drug trials and identify pathways responsible stage I/II breast cancer survive to 5 years; (cancerresearchuk.org; for drug resistance; and what are the limitations of patient-derived wcrf.org)], there is no cure currently available for metastatic breast xenograft models? We briefly outline the areas where the existing cancer, which affects an estimated 40% of UK patients breast cancer models require improvement in light of the increased (breastcancernow.org) and likely accounts for the decline in understanding of the disease process, reflecting the drive towards survival rate to 65% at 20 years post-diagnosis. Genetic more personalised therapies and identification of mechanisms of sequencing endeavours have identified many of the mutations drug resistance. implicated in breast cancer (Nik-Zainal et al., 2016), which may lead to the development of new therapeutic options; however, the KEY WORDS: Breast cancer, Mouse models, GEMM, PDX, CDX, functional role of these alterations in the different subtypes has still SEARCHBreast, EurOPDX to be confirmed, and their distinct roles during disease progression, tumour heterogeneity and dormancy, clarified (Eccles et al., 2013). Introduction Scientists have capitalised on in vivo models as important Clinical management of breast cancer has improved significantly research tools to study the pertinent questions in breast cancer over the past 30 years, with almost 87% of women surviving their research (Fig. 1). By ‘in vivo’ we refer to a living organism and we diagnosis for at least 5 years compared with only 53% of those will restrict our discussions to the mouse, a physiologically relevant diagnosed in the early 1970s (cancerresearchuk.org; accessed system in which to explore cancer initiation, invasion and December 2016). Nonetheless, breast cancer remains the leading metastasis, and which represents an essential step between in vitro cause of cancer-related female death worldwide with more than half systems and clinical studies. Researchers now have access to a broad a million women succumbing to the disease annually (Torre et al., range of mouse models, each with its own strengths and limitations 2016) including around 11,500 in the UK (breastcancernow.org; (see overview in Table 1). A clear understanding of these parameters accessed December 2016). One of the reasons for this is that breast is paramount in order to choose the model best suited to address the cancer is not a single disease entity (Curtis et al., 2012) and ‘one specific research questions posed. SEARCHBreast, an organisation size’ does not ‘fit all’ for clinical management, treatment nor, as dedicated to sharing animal resources (see Box 1), hosted a discussed here, modelling of the disease. Breast cancer is treated workshop (searchbreast.org/workshop3.html) to showcase the based on the receptor status of the tumour, specifically oestrogen contribution these complex models have made to breast cancer research highlighting recent developments and discussions on how shortfalls in existing models could be addressed in the foreseeable 1Academic Unit of Clinical Oncology, University of Sheffield, Sheffield S10 2RX, UK. future. The workshop, open to all UK researchers with an interest in 2Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK. 3Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. breast cancer, involved presentations and discussions from leading groups with broad expertise in utilising breast cancer mouse models *Author for correspondence ([email protected]) in a variety of areas, from disease mechanisms to preclinical trials. K.B., 0000-0002-9304-439X In this workshop-inspired perspective, we highlight recent progress in mouse models of breast cancer, and discuss some of the This is an Open Access article distributed under the terms of the Creative Commons Attribution outstanding issues researchers are grappling with in their pursuit of License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. the best in vivo model for their research question. The article is not Disease Models & Mechanisms 359 REVIEW Disease Models & Mechanisms (2017) 10, 359-371 doi:10.1242/dmm.028274 Fig. 1. Modelling breast cancer through the ages. The figure depicts a First transplantable mouse mammary timeline of key events or developments tumour linea 1903 in the evolution of mouse models of breast cancer over the years. Mouse mammary tumour virus Lowercase letters denote the following 1936 Jax labs show a retrovirus (MMTV) references, to which the reader is causes high incidence of referred for further reading on specific mammary tumoursb milestones: aCardiff and Kenney, 2011; bBittner, 1936; cDeOme et al., 1959; d e Syngeneic transplants Rygaard and Povsen, 2007; Fidler, f g Tumours in mouse mammary glands 1958 1973; Stewart et al., 1984; Muller et al., following orthotopic transplantc 1988; hFu et al., 1993; iBaselga et al., 1998; jXu et al., 1999; kBeckhove et al., 2003; lBehbod et al., 2009; mDeRose First xenograft models of breast cancer et al., 2011; nWhittle et al., 2015; oWurth 1969 Heterotransplantation of human malignant et al., 2015; phttps://www.jax.org/news- d tumours into the nude mouse and-insights/jax-blog/2015/april/the- CDX models for metastasise 1973 next-big-thing-in-cancer-modeling- patient-derived-xenografts-in-humaniz. Spontaneous mammary 1984 adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genesf First germline GEMM to model HER2+ breast cancer 1988 Ectopic rat Neu targeted to mammary gland in a transgenic modelg First orthotopic metastatic breast 1993 cancer PDX fragment transplanted to nude mouse fat padh CDX models show therapeutic benefit of Herceptin in HER2+ breast cancer cellsi 1998 First GEMM to model BRCA1 1999 breast cancerj Patient-derived xenograft (PDX) Efficient engraftment of human 2003 primary breast cancer transplants in nonconditioned NOD/SCID micek MIND model 2009 Dan Medina lab pioneer the mouse intraductal transplant modell All clinically defined subtypes of breast cancer have been established as 2011- 2013 PDX modelsm PDXs as platform for translational 2014 researchn Preclinical model of inflammatory breast cancero 2015 2016 Humanised PDX developed containing human immune cellsp Disease Models & Mechanisms 360 REVIEW Disease Models & Mechanisms (2017) 10, 359-371 doi:10.1242/dmm.028274 Table 1. Advantages and disadvantages of the main types of in vivo murine models of breast cancer Model Advantage Disadvantage Ectopic CDX (human tumour Fast, cheap, technically simple Immunocompromised host cells implanted subcutaneously) Involves human tumour cells Not all subtypes grow Tumour volume is easy to measure with callipers Tumour growing in peripheral site Resectable tumours possible Models advanced disease only Orthotopic CDX (in mammary Appropriate microenvironment Technically more complex than ectopic models gland/fat pad) Tumour size measurable with callipers Immunocompromised host Resectable tumours
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