Article

Mouse models of breast cancer metastasis

Institute of Biochemistry and Genetics, Department of Clinical-Biological Sciences (DKBW), Center of Biomedicine, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland.
Breast cancer research: BCR (Impact Factor: 5.49). 02/2006; 8(4):212. DOI: 10.1186/bcr1530
Source: PubMed
ABSTRACT
Metastatic spread of cancer cells is the main cause of death of breast cancer patients, and elucidation of the molecular mechanisms underlying this process is a major focus in cancer research. The identification of appropriate therapeutic targets and proof-of-concept experimentation involves an increasing number of experimental mouse models, including spontaneous and chemically induced carcinogenesis, tumor transplantation, and transgenic and/or knockout mice. Here we give a progress report on how mouse models have contributed to our understanding of the molecular processes underlying breast cancer metastasis and on how such experimentation can open new avenues to the development of innovative cancer therapy.

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Available online http://breast-cancer-research.com/content/8/4/212
Abstract
Metastatic spread of cancer cells is the main cause of death of
breast cancer patients, and elucidation of the molecular mecha-
nisms underlying this process is a major focus in cancer research.
The identification of appropriate therapeutic targets and proof-of-
concept experimentation involves an increasing number of experi-
mental mouse models, including spontaneous and chemically
induced carcinogenesis, tumor transplantation, and transgenic
and/or knockout mice. Here we give a progress report on how
mouse models have contributed to our understanding of the
molecular processes underlying breast cancer metastasis and on
how such experimentation can open new avenues to the
development of innovative cancer therapy.
Introduction
Breast cancer is the most frequently diagnosed form of
cancer and the second leading cause of death in Western
women [1]. Death, and most of the complications associated
with breast cancer, are due to metastasis developing in
regional lymph nodes and in distant organs, including bone,
lung, liver, and brain [1,2]. As in many other metastatic cancer
types, specific molecular changes occurring within both the
tumor cells and the tumor microenvironment contribute to the
detachment of tumor cells from the primary tumor mass,
invasion into the tumor stroma, intravasation into nearby
blood vessels or lymphatics, survival in the bloodstream,
extravasation into and colonization of the target organ and,
finally, metastatic outgrowth [3,4].
In the recent past, our understanding of breast cancer
progression and metastasis has greatly profited from the use
of genetically modified mouse models and advanced trans-
plantation techniques. Here we describe the currently
employed mouse models of breast cancer metastasis and
how their use has contributed significantly to our
understanding of the molecular processes underlying breast
cancer metastasis.
Mechanisms contributing to breast cancer
metastasis
A critical step towards the generation of mouse models of
breast cancer is the understanding of the molecular pathways
underlying mammary carcinogenesis. Our knowledge on how
breast tumor progression occurs has also been markedly
improved by unraveling the dynamics and the key factors of
mammary gland development.
Mammary gland development
Mouse breast tissue undergoes continuous changes through-
out the lifespan of reproductively active females, mediated
mainly by interactions between the mammary epithelium and
the surrounding mesenchyme (Figure 1). The mammary bud
develops by forming a network of branched ducts invading
into the mammary fat pad [5]. With the release of ovarian
hormones, terminal end buds are formed. They represent the
invading front of the ducts and they are able to proliferate, to
extend into the fat pad, and to form branches. During
pregnancy and lactation, hormone-induced terminal differen-
tiation of the mammary epithelium into milk-secreting lobular
alveoli takes place. After weaning, the secretory epithelium of
the mammary gland involutes into an adult nulliparous-like
state by apoptosis and redifferentiation. During these proces-
ses, the developing mammary gland has the ability to induce
angiogenesis to adjust for blood supply and is protected
against premature involution; it is therefore resistant to
apoptosis [6]. Interestingly, proliferation, invasion, angio-
genesis, and resistance to apoptosis are all features that are
abused during the etiology of breast carcinogenesis.
Review
Mouse models of breast cancer metastasis
Anna Fantozzi and Gerhard Christofori
Institute of Biochemistry and Genetics, Department of Clinical-Biological Sciences (DKBW), Center of Biomedicine, University of Basel, Mattenstrasse
28, CH-4058 Basel, Switzerland
Corresponding author: Gerhard Christofori, gerhard.christofori@unibas.ch
Published: 26 July 2006 Breast Cancer Research 2006, 8:212 (doi:10.1186/bcr1530)
This article is online at http://breast-cancer-research.com/content/8/4/212
© 2006 BioMed Central Ltd
COX = cyclo-oxygenase; CSF = colony-stimulating factor; CTGF = connective tissue growth factor; ECM = extracellular matrix; EGF = epidermal
growth factor; EMT = epithelial–mesenchymal transition; IGF = insulin-like growth factor; IL = interleukin; MEKK = MAP kinase/ERK kinase kinase;
MMP = matrix metalloproteinase; MMTV = murine mammary tumour virus; PTHrP = parathyroid hormone-related protein; PyMT = polyoma middle T
antigen; SDF = stromal cell-derived factor; TGF = transforming growth factor; VCAM = vascular cell adhesion molecule; VEGF = vascular endothe-
lial growth factor.
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Breast Cancer Research Vol 8 No 4 Fantozzi and Christofori
Transformation and metastasis
Mammary gland morphogenesis and branching involve the
regulatory function of several signaling pathways, including
signaling by Wnt family members [7], transforming growth
factor-β (TGF-β) [8], insulin-like growth factor-I (IGF-I) [9],
and epidermal growth factor (EGF) and others [10]. These
pathways are frequently activated during the tumorigenic
process by mutation or gene amplification, thus allowing the
mammary epithelium to expand, proliferate, and invade neigh-
boring tissue. The cross-talk and interactions between tumor
cells and the surrounding stroma, the extracellular matrix
(ECM), and infiltrating cells of the immune system are con-
stantly modulating tumor development. The mammary stroma,
composed of pre-adipocytes, adipocytes, fibroblasts, endo-
thelial cells, and inflammatory cells, contributes functionally to
mammary gland development [6]. In a similar manner,
tumor–stroma interactions, occurring via soluble growth
factors, cytokines and chemokines, remodeling of the extra-
cellular matrix, or direct cell–cell adhesion, are critical for
tumor growth, migration, and metastasis. Alteration of the
expression or function of adhesion molecules responsible for
the adhesion of breast cancer cells to themselves, to stromal
cells, or to tumor matrix, including integrin family members,
immunoglobulin-domain cell adhesion molecules (such as L1
and NCAM), cadherin family members, or other cell surface
receptors (such as CD44), contributes predominantly to late-
stage tumor progression and metastatic dissemination of
cancer cells [11,12].
The formation of new blood vessels (angiogenesis) is crucial
for the growth and persistence of primary solid tumors and
their metastases, and it has been assumed that angiogenesis
is also required for metastatic dissemination, because an
increase in vascular density will allow easier access of tumor
cells to the circulation. Induction of angiogenesis precedes
the formation of malignant tumors, and increased vasculari-
zation seems to correlate with the invasive properties of
tumors and thus with the malignant tumor phenotype [13]. In
fact, angiogenesis indicates poor prognosis and increased
risk of metastasis in many cancer types, including breast
cancer [14]. With the recent identification of lymphangio-
genic factors and their receptors it has also been possible to
Figure 1
Schematic representation of epithelial–stromal interactions during mammary gland development. The mammary bud originates at the embryonic
level and starts proliferating after birth. Pubertal hormones drive the invasion of the fat pad by the generation of epithelial ducts and terminal end
buds (TEB). Proliferation and side branching continues until epithelial ducts fill the adult mammary gland. Pregnancy hormones induce the full
development and proliferation of the mammary gland and the transformation of the lobular alveoli into milk-secreting ducts. After lactation the
mammary gland involutes to return to a nulliparous-like state via apoptosis, redifferentiation and remodeling processes. C/EBP, CCAAT-enhancer-
binding protein; CSF, colony-stimulating factor; DDR, discoidin domain receptor; ECM, extracellular matrix; HSPG, heparan sulfate proteoglycan;
GH, growth hormone; IGF, insulin-like growth factor; IRF, interferon regulatory factor; MMP, matrix metalloproteinase; NFκB, nuclear factor-κB;
Ptc-1, patched-1; TGF, transforming growth factor; TIMP, tissue inhibitor of metalloproteinases.
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    • "A common model for breast cancer are transgenic mice expressing the polyoma virus middle T oncoprotein (PyMT) within breast epithelial cells. In this model tumor formation is spontaneous and occurs in all transformed mice [12]. Immune cells like macrophages significantly contribute to all phases of cancer development, a process known as cancer immunoediting [13, 14]. "
    [Show abstract] [Hide abstract] ABSTRACT: Activation of hypoxia-inducible factor (HIF) and macrophage infiltration of solid tumors independently promote tumor progression. As little is known how myeloid HIF affects tumor development, we injected the polycyclic aromatic hydrocarbon (PAH) and procarcinogen 3-methylcholanthrene (MCA; 100 μg/100 μl) subcutaneously into myeloid-specific Hif-1α and Hif-2α knockout mice (C57BL/6J) to induce fibrosarcomas (n = 16). Deletion of Hif-1α but not Hif-2α in macrophages diminished tumor outgrowth in the MCA-model. While analysis of the tumor initiation phase showed comparable inflammation after MCA-injection, metabolism of MCA was impaired in the absence of Hif-1α. An ex vivo macrophage/fibroblast coculture recapitulated reduced DNA damage after MCA-stimulation in fibroblasts of cocultures with Hif-1α LysM-/- macrophages compared to wild type macrophages. A loss of myeloid Hif-1α decreased RNA levels of arylhydrocarbon receptor (AhR)/arylhydrocarbon receptor nuclear translocator (ARNT) targets such as Cyp1a1 because of reduced Arnt but unchanged Ahr expression. Cocultures using Hif-1α LysM-/- macrophages stimulated with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA; 2 μg/ml) also attenuated a DNA damage response in fibroblasts, while the DNA damage-inducing metabolite DMBA-trans-3,4-dihydrodiol remained effective in the absence of Hif-1α. In chemical-induced carcinogenesis, HIF-1α in macrophages maintains ARNT expression to facilitate PAH-biotransformation. This implies a metabolic activation of PAHs in stromal cells, i.e. myeloid-derived cells, to be crucial for tumor initiation.
    Full-text · Article · Mar 2016 · Oncotarget
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    • "Mouse models of metastatic cancer are only beginning to capture this diversity, and new and improved models to study metastasis would greatly benefit the metastasis research field. Tissuespecific oncogene expression (and/or tumor-suppressor loss) has been used to induce metastatic cancer in many tissues, including liver (Shachaf et al. 2004; Lewis et al. 2005), breast (reviewed in Fantozzi and Christofori 2006; Vernon et al. 2007; Bos et al. 2010), colon (reviewed in Heijstek et al. 2005), lung (Meuwissen et al. 2003; Rapp et al. 2009; Winslow et al. 2011), skin (Landsberg et al. 2010; Damsky et al. 2011; Schiffner et al. 2012), pancreas (Tevethia et al. 1997; Hingorani et al. 2005; Bardeesy et al. 2006; Rhim et al. 2012), ovary (reviewed in Sale and Orsulic 2006), and prostate (Gingrich et al. 1996; Han et al. 2005; Moore et al. 2008). In transgenic cancers, metastatic sites are often identical in different models, perhaps reflecting tropism in the tissue of origin of the primary tumor. "
    [Show abstract] [Hide abstract] ABSTRACT: Metastasis is often modeled by xenotransplantation of cell lines in immunodeficient mice. A wealth of information about tumor cell behavior in the new environment is obtained from these efforts. Yet by design, this approach is “tumor-centric,” as it focuses on cell-autonomous determinants of human tumor dissemination in mouse tissues, in effect using the animal body as a sophisticated “Petri dish” providing nutrients and support for tumor growth. Transgenic or gene knockout mouse models of cancer allow the study of tumor spread as a systemic disease and offer a complimentary approach for studying the natural history of cancer. This introduction is aimed at describing the overall method-ological approach to studying metastasis in genetically modified mice, with a particular focus on using animals with regulated expression of potent human oncogenes in the breast.
    Preview · Article · Feb 2016
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    • "Also intratumoral androgens concentrations were reported to be significantly higher in breast carcinoma [20], and androgen-producing enzymes, such as 17bHSD5 that converts circulating androstenedione to testosterone, and 5a- reductase type 1, which reduces testosterone to DHT, were expressed [21]. The development of xenografts has been a useful tool for improving our understanding of breast cancer progression and metastasis [22][23][24]. The majority of breast cancer xenografts are performed on female mice. "
    [Show abstract] [Hide abstract] ABSTRACT: Canine inflammatory mammary cancer (IMC) shares clinical and histopathological characteristics with human inflammatory breast cancer (IBC) and has been proposed as a good model for studying the human disease. The aim of this study was to evaluate the capacity of female and male mice to reproduce IMC and IBC tumors and identify the hormonal tumor environment. To perform the study sixty 6–8-week-old male and female mice were inoculated subcutaneously with a suspension of 10 6 IPC-366 and SUM149 cells. Tumors and serum were collected and used for hormonal analysis. Results revealed that IPC-366 reproduced tumors in 90% of males inoculated after 2 weeks compared with 100% of females that reproduced tumor at the same time. SUM149 reproduced tumors in 40% of males instead of 80% of females that reproduced tumors after 4 weeks. Both cell lines produce distant metastasis in lungs being higher than the metastatic rates in females. EIA analysis revealed that male tumors had higher T and SO4E1 concentrations compared to female tumors. Serum steroid levels were lower than those found in tumors. In conclusion, IBC and IMC male mouse model is useful as a tool for IBC research and those circulating estrogens and intratumoral hormonal levels are crucial in the development and progression of tumors.
    Full-text · Article · Jan 2016
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