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Breast cancer

Every year around 2.3 million women are diagnosed with breast cancer which causes over 685 thousand deaths each year. As of the end of 2020, there were 7.8 million women alive who were diagnosed with breast cancer in the past 5 years, making it the world’s most prevalent cancer. Breast cancer occurs in every country of the world in women at any age after puberty but with increasing rates in later life. Roughly half of all breast cancers occur in women with no specific risk factors other than sex and age. Men can also get breast cancer, but it only represents 0.5 to 1% of cases.

Breast cancer mortality changed little from the 1930s through to the 1970s when surgery alone was the primary mode of treatment (radical mastectomy). Improvements in survival began in the 1990s when countries established early detection programmes for breast cancer that were linked to comprehensive treatment programs, including effective medical therapies. Early detection and good treatments mean that survival rates have increased to about 80% in more developed regions. Animal studies led to the development of tamoxifen, one of the most successful treatments, and more recently Herceptin (trastuzumab) and aromatase inhibitors.

Causes
Drug Development
Tamoxifen
Aromatase inhibitors
Herceptin
PARP inhibitor
Animal models
Breast cancer in animals
References

 

Causes

Like most cancers, the risk of developing breast cancer increases with age. However, there are several factors that affect the likelihood of developing breast cancer.

The risk for developing breast cancer approximately doubles if a parent or sibling has been diagnosed with the disease, for example from a 1 in 10 chance to a 1 in 5 chance. This likelihood increases further if there have been several cases in the family or if it has been diagnosed at a young age.

A very strong family history can indicate a faulty gene as a major factor. The most common genes that patients are tested for are BRCA1 and BRCA2 - a fault in either of these genes can raise the risk of breast cancer to 45-90%2. Similarly, tests are available to check for faulty TP53 and PTEN genes. However tests have not developed for many more genes known to be linked to breast cancer, including CASP8, FGFR2, TNRCP, MAP3K1, rs4973768, LSP1, CHEK2, ATM, BRIP1 and PALB2.

Post-menopausal women with high levels of the sex hormones oestrogen and testosterone have a 2 to 3 times higher risk of developing breast cancer. Studies have also shown that hormone replacement therapy (HRT), taken by women to relieve symptoms of menopause, also increases the risk of breast cancer3. Oestrogen levels may also explain why women who have more children at an earlier age and breastfeed have a reduced risk of breast cancer.

Drug development

Over the years, numerous drugs have been developed to fight breast cancer. Personalised medicine, in particular, has achieved considerable success in the treatment of breast cancers. 

Commonly used targeted drugs for ERα-positive metastatic breast cancer include anti-oestrogens (e.g., tamoxifen and fulvestrant), aromatase inhibitors (e.g., letrozole and anastrozole), CDK4/6 inhibitors (e.g., palbociclib, ribociclib, and abemaciclib), and PI3Kα inhibitors.

For HER2-positive breast cancer patients, trastuzumab and pertuzumab are the most effective agents. TNBC patients are usually treated with chemotherapy, including anthracyclines, taxanes, and platinum, and targeted therapies, including PARP inhibitors (e.g., olaparib and talazoparib) for BRCA1/2 mutation carriers and anti-PD-L1 mAb (e.g., atezolizumab) for PD-L1-positive patients.

Different breast cancer animal models have been used for drug efficacy evaluation, biomarker identification, and resistance research. Currently, transplantation and transgenic models are the most common. Xenograft models and genetically modified models are also widely used to elucidate the underlying mechanisms of drug resistance, pathogenesis of breast cancer and metastasis, and drug efficacy and toxicity. Spontaneous and induced breast cancer models, however, are rarely used in routine screening of anti-tumour drugs.

Tamoxifen

Normal breast development is controlled by hormones, including oestrogens and progesterone. These hormones and their roles in fertility and development were discovered during the 1930s through fundamental research in animals. However, even before hormones were discovered, animal experiments showed that removing ovaries from mice reduced their likelihood of developing breast cancer4. Further evidence for their role in the development of some cancers came in the 1950s, when researchers discovered that hormone changes can induce breast tumours in rats.

Tamoxifen emerged from a research programme aimed at the development of an anti-oestrogen oral contraceptive. However, tamoxifen actually boosted fertility and was marketed as an inducer of ovulation5. Tamoxifen has opposing effects in different species and in different tissues in the body, either increasing or decreasing the effects of oestrogen. Its oestrogen boosting activity in the ovaries make it unsuitable for a contraceptive, but its role in reducing oestrogen in breast tissue ultimately proved much more interesting as a treatment for breast cancer6.

Although the significance of this is clear today thanks to animal testing, in the late 1960s breast cancer was not a significant issue and tamoxifen did not initially generate much excitement7. It was first licensed for use in 1973, even though little was known about how effective it was and who the target population were. Studies using the dimethylbenzathracene (DMBA)-induced rat mammary carcinoma model allowed researchers to systematically study the anti-tumour effects of tamoxifen and determine how useful it would be to patients. Studies in breast cancer cell cultures showed that high concentrations of tamoxifen would kill the cancer8 and given medical concerns about the cancer developing resistance, initial clinical trials only ran for one year, which showed tamoxifen to be ineffective. However, tests in the rat model showed that one month treatment (equivalent to a year in humans) only delayed the onset of cancer9 10, while five months of small doses could prevent it completely11 12. Longer trials were then conducted in humans, which showed it to enhance survival rates and prevent nearly half of cancers13.

An analysis in 2000 showed that there was an unprecedented fall of about 30% in the death rate from breast cancer in the UK in the 1990s. This improvement is due in part to use of tamoxifen, which was then in widespread use in the UK - earlier than in the USA or other European countries.

Tamoxifen has also been used to develop alternatives to using animals in breast cancer research, by proving that human tumour cells grown in laboratory cell cultures will respond to the same drugs that work in patients. Without the animal work, it would have been difficult if not impossible to demonstrate that the cell culture results were relevant and reliable.

In early 2013, it was shown that tamoxifen reduces the chances of developing breast cancer by 38% in high-risk women14. Taking tamoxifen for 5 years provides this protective effect for another 5 years after treatment ends. This study was based on previous research on rats and mice15, which showed that tamoxifen provided long-lasting protection against breast cancer and many other cancers. When given tamoxifen from an early age for life it increases the rats' risk of liver cancer, but does not increase the risk when given at an older age, which is more applicable to most human patients.

Aromatase inhibitors

Aromatase inhibitors block production of the oestrogen, ‘starving’ breast cancer cells of growth stimuli. Professor Angela Brodie of the University of Maryland School of Medicine developed the aromatase inhibitors16 and tested them in mice, comparing them with tamoxifen, then the gold-standard treatment for ‘oestrogen-receptor-positive’ cancers.

This research showed how animal models can predict patient response not just to a particular medicine, but to different combinations of therapy – a critical factor in cancer treatment. For example, animal studies with combinations of tamoxifen and aromatase inhibitors did not show any improvement over established treatments.

Aromatase inhibitor therapy alone was shown to be the most effective17, and after clinical trials aromatase inhibitors were approved for use in patients with oestrogen-fuelled breast cancer. Later studies with patients showed that sequential treatment with tamoxifen and then the aromatase inhibitor exemestane improved survival rates for this type of breast cancer, and could save a further 1,300 lives a year in the UK alone18.

In December 2013, the IBIS II trial of 4000 post-menopausal women showed that taking the aromatase inhibitor anastrozole (Arimidex) for 5 years reduces the risk by 50% for high-risk women19. Not only did this provide better protection than tamoxifen, but it also had fewer side-effects. This has led to calls for changes in the guidance for doctors when considering preventative treatment for post-menopausal women. Because it blocks production of oestrogen, anastrozole is only suitable to give to women after menopause, while tamoxifen is suitable both pre- and post-menopause.

Aromatase inhibitors are linked with reduced bone density, potentially making it unsuitable for women with severe osteoporosis. Bone-strengthening drugs called bisphosphonates can be used to prevent bone density problems in women at risk.

Herceptin

Herceptin (trastuzumab) was the first humanised monoclonal antibody used to successfully treat cancer. Its development was another landmark in breast cancer research. It is described as humanised because it is an antibody that was originally produced in a mouse, but has altered to make it more similar to human antibodies and so less likely to trigger an immune reaction against it. By going through this process, the antibody can be considered to be 95% human and 5% mouse, where the mouse region is the important part for functioning.

Herceptin was produced as an antibody to target the HER2 protein, which helps breast cancer cells to grow. By blocking HER2 from working, Herceptin can help to destroy cancers that produce a lot of HER2 and need it to survive. Over-expression of HER2 occurs in 20% to 30% of breast tumours.

The discovery of HER2 was published in 1982 after researchers studied neurological tumours in rats20. In 1985, the first monoclonal antibodies to target against HER2 in mice showed they could reduce tumour growth and prolong survival21.

Herceptin was developed in 1991 and is produced using Chinese hamster ovary cells. Trials in animals and humans revealed the benefits of the treatment and which women should receive it. For example, Herceptin is not routinely recommended for pregnant or nursing women after studies showed that monkeys pass it through to the foetus and secrete it in milk22. Following these tests, Herceptin was first approved in 1998.

Herceptin was originally given after initial treatment of metastatic breast cancer to help to prevent the cancer from returning, but is now also applied to early-stage breast cancer. In 2005, researchers reported a 50% fall in the rate of breast cancer recurrence after one year of treatment23. This degree of benefit in early breast cancer was the largest reported since the introduction of tamoxifen.

For more information, see this audio slideshow on Herceptin or download the Powerpoint file from here.


 

PARP Inhibitor

Based on the Brca1 and p53 conditional double knockout mouse model of hereditary breast cancer, Rottenberg et al. (20072008) revealed that breast tumours lacking BRCA1 are highly sensitive to the PARP inhibitor AZD2281 alone and in combination with platinum drugs.

These results accelerated the clinical application of PARP inhibitors in patients with BRCA1 gene deletion or mutation. Jaspers et al. and Gogola et al.  recently used the same model to illustrate how tumours become resistant to PARP inhibitors. Furedi et al. used this model to demonstrate that a compound, pegylated liposomal doxorubicin, increases the recurrence-free survival rate (by six times) and overall survival rate (by three times) compared with traditional doxorubicin.

Animal models

Animal models have played a vital role in the history and development of basic and translational breast cancer research in humans. According to different requirements, different animal models have been constructed to simulate the occurrence and development of human breast cancer.

 

Non-mammalian models

Non-mammalian animals, such as Caenorhabditis elegansDrosophila, zebrafish, and chickens, are frequently used to mimic breast cancer cell growth, migration, and metastasis. The benefits of these animals include rapid experimental cycles and low costs because of their short reproductive cycles. However, these animals - and their organs - are different from humans and appear to lack many homologous genes and physiological structures.

Chickens and zebrafish have been applied to study tumour angiogenesis. For example, Mercatali et al. (2016) injected primary cultured bone metastases cells from breast cancer patients into zebrafish embryos to study their metastatic potential. Ren et al. (2017) transplanted fluorescent protein and chemically labelled human breast cancer cells into zebrafish embryos and visualized the spatiotemporal processes of cancer cell spread, invasion, and metastasis.

 

Mammalian models

Rodents are the most popular animals for breast cancer research, especially mice due to their small size, low cost, short generation time, diversity of inbred strains and mature gene editing technology. The establishment of mouse models of breast cancer has greatly assisted in the research, prognosis, clinical drug screening, and development of new therapeutic methods for breast cancer, especially for studies on breast cancer metastasis mechanisms and the discovery of targeted drugs.

Mice are also similar to humans in terms of anatomy, physiology, and genetics. However, breast cancer mouse models also have drawbacks. For instance, mice can tolerate higher doses of drugs than humans, meaning that drug concentrations in mice can reach higher levels than in humans, which means that some drugs that are crowned with success in mice, fail in humans. Moreover, mouse breast cancer metastasis usually occurs in the lung, and not the lymph node, liver, bone, and brain, like in humans.

Other rodents (e.g., rats, hamsters, moles), dogs, cats, pigs, tree shrews, and non-human primates are also commonly used for breast cancer research. Non human primates (NHPs), such as monkeys, are similar to humans and have been widely used to study human diseases, including breast cancer. However, due to the low incidence of spontaneous tumours, long incubation periods, and high costs, NHPs have not been widely used in cancer research. Dogs, on the other hand, have been found to be a suitable large-animal model for human breast cancer. Spontaneous breast tumours are very common in female dogs, accounting for 50% of all tumours diagnosed. In addition, tree shrews are increasingly used due to their closer evolutionary relationship to primates than to rodents. (Fan et al., 2019Xiao et al., 2017). Tree shrews are a new experimental animal model and are considered advantageous notably because they are small in body size and highly productive (Xia et al., 2012Xiao et al., 2017 (Fan et al., 2013). Most importantly, tree shrews develop spontaneous breast cancers with high frequency (Xia et al., 2014). Spontaneous tumours in tree shrews were actually reported as early as the 1960s (Elliot et al., 1966). Breast tumours can also be induced in tree shrews by chemical carcinogens and oncogenes.

Overall disadvantages of using mammals for breast cancer research include long experimental periods and high costs.

 

Large animal models

Breast cancer can be modelled with many small animal models. However, none of these models can overcome the limitation of inadequate subject size which hinder the development of some diagnostic and interventional technologies. Sometimes, research requires a human-sized model to understand how clinically relevant tumour size and tissue thickness affect the performance of an experimental technology.

In addition, pharmacokinetic parameters (including absorption, distribution, metabolism, and excretion) can be vastly different between a 20 g mouse and a 70 kg patient. Testing the effect of an infused chemical entity (e.g., a novel anti-tumour agent) in a small tumour model may result in an inaccurate conclusion secondary to these pharmacokinetic differences.

While large animal breast cancer models are unlikely to match the proven utility and ease-of-use of rodent and murine models, the availability of validated large animal breast cancer models could provide additional tools for breast cancer research, including availability of human-sized subjects and breast cancer models with greater biologic relevance.

Most of the older work on large animal modelling of breast cancer has focused on feline and canine subjects. Of note, non-human primates have not been commonly utilized in breast cancer or other cancer research. Recently, developmental work on porcine breast cancer models has emerged, with promising data from both orthotopic implantation strategies and genetic editing.

Breast cancer in animals

Animal models are involved in breast cancer research from the study of the biological mechanisms at play to the development of new therapies. Breast cancer animal models are useful in many different contexts and will continue to contribute to our understanding of disease progression, treatment response, and resistance mechanisms.

Breast cancer is highly heterogeneous and no breast cancer animal model is perfect. Therefore, no single model can fully reflect the heterogeneity and drug reactivity of all breast cancers. Each animal model can only imitate certain aspects of human breast cancer. Every rodent model has advantages and disadvantages, and the selection of appropriate rodent models with which to investigate breast cancer is a key decision in research. It is necessary to combine different models to understand breast cancer biology and develop prevention and therapy methods.

The xenograft model remains the primary tool for therapeutic drug discovery and evaluation. However, mouse allograft models, humanized PDX models, and genetically modified animal models will play increasingly important roles. Overall, in the past century, rodent models have proved to be powerful tools in improving knowledge of the underlying mechanisms and genetic pathways of breast cancer and have also created approaches for modelling clinical tumour subtypes and developing innovative cancer therapies.

 

Spontaneous models

Spontaneous tumours occur naturally in animal populations. The most important characteristic of spontaneous breast cancer is that the animals have not been artificially treated to induce the cancer. As such, spontaneous cancers tend to be similar to human’s in terms of aetiology.

Spontaneous breast tumours are similar to human tumours because they occur naturally in genetically heterogeneous populations. However, their study is usually difficult in the laboratory context. Their incidence rates are low, with long latency, lengthy experimental periods, and non-synchronization. Therefore, spontaneous breast cancer animal models are usually used for studying cancer aetiology and treatment.

Spontaneous breast tumours have been frequently observed in rodents, however their incidence and frequency vary considerably among the different strains. Some are more prone to develop spontaneous tumours compared to others, linked to their genetic makeup.

In addition to rodents, spontaneous breast cancer has been reported in large animals, such as dogs, cats, tree shrews, and monkeys. Canines, in particular, are of great value in studies as they are outbred, large in size, exhibit a high incidence of spontaneous breast cancer, live in similar environments as humans, and have an intact immune system. Dogs and humans also show more than 80% genetic similarity and their cancers tend to share histological, morphological and clinical characteristics. Furthermore, canine breast cancers are frequently observed in pet hospitals and are often treated with therapies or under clinical trials.

 

Induced models

To increase breast tumour incidence rates and accelerate tumorigenesis, scientists can artificially cause cancer in animals. The animals are treated with chemical, physical, and biological carcinogens through oral administration, injection, and whole-body treatment. The most common method is administration of 7,12-dimethylbenz(a) anthracene (DMBA) or N-methyl-N-nitrosourea (MNU).

The advantages of induced breast cancer animal models include relatively high incidence rates, short latencies, and more reliable predicted results compared with spontaneous breast cancer animal models. However, they also have low efficiencies, long incubation times, different incidence times, and different pathological characteristics. Breast tumours induced by carcinogens are usually hormone-dependent adenocarcinomas. In addition, number of tumours, latency, and histological type in animals can be affected by age, reproductive history, and the host's endocrine environment when exposed to carcinogens. Overall, induced breast cancer animal models are used for studies on aetiology and prevention.

 

Chemical carcinogens

In mice, DMBA, 3,4-benzopyrene, 3-methylcholan-threne (MCA), 1,2,5,6 dibenzanthracene, and urethane have been used to induce breast cancer. Most chemically induced breast tumours in mice are adenomas and type B adenocarcinomas.

In rats, DMBA, MNU, MCA, 2-acetylamino-fluorene, 3,4-benzopyrene, ethylnitrosourea, and butylnitrosourea are widely used to induce breast cancer. DMBA and MNU-induced rat breast cancers are mostly hormone dependent. The most common method for generating induced rat breast cancer models is to treat Sprague-Dawley (SD) or Fischer 344 rats with DMBA or NMU, usually by intravenous, subcutaneous, or intragastric administration. NMU-induced primary rat tumours are similar to ERα-positive low-grade human breast cancer and a good model of human breast cancer progression.

 

Physical carcinogens

Breast cancer can also be induced by physical approaches, such as ionizing radiation. In rats, X-ray or neutron radiation can induce breast cancer by whole-body or segmental irradiation. Among rat strains, SD and Lewis rats are most susceptible to radiation-induced tumorigenesis, whereas AxC, Fisher, Long-Evans, and Wistar/Furth rats are less susceptible. Mammary tumours from irradiated rats are usually hormone-dependent adenocarcinomas or fibroadenomas.

 

Biological carcinogens

Biological induction of breast cancer mainly relies on lentiviruses to overexpress oncogenes or silence tumour suppressor genes in experimental animals. This technology was originally developed by Professor Yi Li from the Baylor College of Medicine. His team developed two new retrovirus-based systems to study the role of specific genes in tumorigenesis.

Both methods insert oncogenes into the somatic cells in vivo to cause cancer. In the first method chicken DF-1 cells are transfected with a plasmid encoding a replication-competent subgroup of avian virus vector RCAS to produce a high titer virus who can attach to the TVA receptor on the cell surface of avian cells. As such, these avian retroviruses are generated to infect mice that are modified to express TVA. Once infected the mice develop various cancer models, including breast cancer. The RCAS virus can be directly injected into the glands of TVA transgenic mice to induce breast tumours. Infected mice develop tumours in all infected glands within three weeks.

The second method is based on the FUCGW lentiviral vector. The gene is stably introduced into the mouse mammary gland by injecting a FUCGW lentiviral vector with the gene of interest to construct a breast cancer model. Compared with the RCAS-TVA system, lentiviruses can infect any cells and can accommodate larger inserts

 

Transplanted models

Breast cancer in animals can also be induced with the transplantation of spontaneous or induced breast cancer tissues or cells. The transplantation model has the advantages of short cycles, low costs, small variations, and high tumour formation rates.

In 1911, the first transplantable mouse mammary tumour line and the epithelial origin of a spontaneous mammary tumour were described by Haaland. 

Currently, the most popular animal model for testing new therapies is the transplantation model, especially the human xenograft model. According to the source of the transplant, models can be divided into allograft and xenograft, with the latter requiring immunodeficient mice.

 

Allograft models

Spontaneous or induced breast cancer cell lines can be transplanted into the same genetic strain with normal immune function. Several transplantable animal breast cancer cell lines have been established, most of which are derived from mice. Most mouse cell lines are derived from spontaneous breast tumours in inbred and genetically engineered mice. Additionally, several rat breast cancer cell lines, such as UHKBR-01 and RM22-F5, are available for allograft.

Although allograft breast cancer models have several advantages, such as multiple characterised cell lines, rapid growth and metastasis, and immune-component microenvironment, these models also have limitations, mostly linked to the fact that the transplanted cancer cells are not from humans.

 

Xenograft models

Cancer cells can be transplanted - subcutaneously, intravenously, cardiacly, and orthotopically - and grown in immunodeficient mice, such as nude mice (lacking T cells), NOD-SCID mice (lacking T and B cells), and NSG mice (lacking T, B, and natural killer cells and macrophages). Recently, researchers have been able to circumvent the need for immunodeficient animals. Indeed, tumours in immunodeficient mice cannot faithfully copy the microenvironment of human tumours, which makes these models unsuitable for immunotherapy. They developed a humanized patient-derived xenograft model, which recapitulates the human immune system.

Patient-derived xenograft (PDX) models are becoming increasingly popular as they are directly derived from human tumour specimens and have never been cultured in vitro. Because most breast cancer cell lines have been grow in vitro for a long time, they can differ from primary tumours in terms of genetic aberrations, gene expression patterns, pathological characteristics, drug responses, and tumour microenvironments. PDX Xenografts, on the other hand, are very close to patients in terms of genetic abnormalities, gene expression profiles, pathological parameters, metastatic potential, and drug response.

PDX models can predict clinical outcomes and have been used in preclinical drug assessment, biomarker identification, biological research, and personalised medicine. The first xenograft breast cancer model was reported in 1962 via the heterotransplantation of human breast cancer into an immune-deficient mouse. Many institutions now build their own PDX model libraries. For example, the Novartis Pharmaceuticals drug screening tool released in 2015 contains more than 1 000 PDX models; NCI contains more than 300 PDX models; and EurO PDX consists of 16 European research institutions and 1 500 models. These libraries provide great convenience for the screening of preclinical drugs and basic research.

However, PDX models are also expensive, difficult, and time-consuming to prepare because NSG mice and humanised matrix components are usually required. Researchers have engineered solutions that bypass the in vivo component and built patient-derived organoids (PDOs). These are derived from primary human tumours and cultured in vitro, which preserves the complex histological architecture and heterogeneity of tumour tissue. PDOs can solve the long cycle and high cost of PDX model establishment and are also suited for mass anti-tumour drug screening, including for breast cancer.

  

Genetically engineered animal models

The development of genetically engineered animal models offered a great leap in understanding the genetic basis of breast cancer. In genetically engineered animal models, the target is clear, the animal's immune function is usually intact, and the genetic alterations are similar to breast cancer patients. Therefore, they are widely used for aetiology and preventive studies. However, the breast tumours developed from genetically engineered animals tend to be different from human breast tumours in histology. Moreover, they are expensive and time consuming.

The first report of a transgenic mouse model of breast cancer, Oncomouse, occurred in 1984. The Philip Leder research group generated transgenic mice using mouse mammary tumour virus (MMTV)/c-myc fusion gene expression. The mice developed mammary adenocarcinomas spontaneously, and 3 years later, they produced transgenic mice with co-expression of MMTV/v-Ha-ras and MMTV/c-myc genes, which resulted in a dramatic and synergistic acceleration of tumour formation. These milestones established an entirely new research tool with which to explore the genetic processes of breast cancer. The first transgenic mouse model of HER2-positive breast cancer, reported in 1988, represented another milestone in breast cancer research.

 

Transgenic breast cancer animal models

Genetically engineered animal models of breast cancer are created by inserting oncogenes into the animal’s tissue using transgenic technology which causes the animals to develop cancer. Overexpression of breast-specific oncogenes has been the primary approach for studying breast cancer in transgenic mice. These models can develop breast carcinoma in situ, and even distant metastasis at later stages. Conventional transgenic mice use tissue-specific promoters to allow for tissue-specific expression of these oncogenes. Multiple copies of the oncogenes are then randomly integrated into the mouse genome.

Promoters, used to target the breast tissue, commonly used in transgenic animal models of breast cancer include mouse mammary tumour virus long terminal repeat (MMTV-LTR), derived from a virus that causes mammary tumours in mice, and whey acidic protein (WAP) promoters. The MMTV promoter is hormone-activated, hence its activity is significantly enhanced during pregnancy, and drives transgene expression in ducts and alveolar cells at all developmental stages of the mammary gland. Drawbacks of this promoter include uneven mosaic pattern activation and leakage. The WAP promoter is only active in the breast during mid-pregnancy. It is activated by lactogenic hormones in mouse breast tumours, and preferentially drives the expression of transgenes in alveolar cells during small alveolar differentiation. Both promoters can be used to achieve specific expression of foreign genes in breast epithelial cells to avoid tumour induction in other organs. Jacksons Laboratories were the first to show in 1936 that a retrovirus can cause a high incidence of mammary tumours in mice.

 

Gene knockout breast cancer animal models

In addition to transgenic animal models, there are also tumour suppressor knockout breast cancer animal models. Tumour suppressor genes are safeguards of the organisms. They help prevent cancers from developing. With the development of technology, spatiotemporal specific knockout and transgene expression can be achieved. Breast tissue-specific knockout of tumour susceptibility genes in the genome of experimental animals can create breast cancer models.

Knockout animal models efficiency has been vastly improved by the CRISPR-Cas9 system. It has been used to generate genetically modified mouse models, including knockout (KO) and knockin(KI) animal models and somatic genome editing models. Compared with traditional gene targeting strategies, CRISPR-Cas9 greatly improves efficiency and can knock out multiple genes at the same time.

 

Compound transgenic breast cancer animal models

It is possible to combine both the transgenic animal models with allow for the overexpression of specific oncogenes, and the knockout animal models that weaken the genetic capacities of an organism to defend against tumours. In combination, complex transgenic breast cancer mouse models can be created. Study of these models not only highlights specific genetic events in disease progression but also the complex, multi-step nature of breast cancer progression.

 

Breast cancer metastasis animal models

Metastasis is the leading cause of death in breast cancer patients. Priority sites for human breast metastasis include the lymph node, bone, lung, liver, and brain. After human breast cancer cells are injected into blood circulation of immunodeficient mice, distant metastases may develop. For example, intravenous tail vein injection primarily causes lung metastasis, whereas intracardiac injection results in bone metastases. This approach bypasses the early steps of migration and invasion and can generate distant metastasis more efficiently.

 

There are animal models for lung, bone, liver and brain metastasis of breast cancer that have been developed, among others.

 

Non animal models

Breast cancer research currently relies heavily on animal models, which, however, have limitations in capturing important cancer traits. For this reason, research is gradually moving towards the use of advanced non-animal models that can at times more faithfully represent the characteristic heterogeneity peculiar to human breast cancer.

A study, reviewing extensively 120,000 peer-reviewed publications of scientific literature, identified 935 innovative, relevant, and promising advanced non-animal models of breast cancer. A detailed description of all these 935 non-animal models for breast cancer research as well as information on their applications and biological relevance has been gathered in a unique knowledge collection. This collection of models is freely available for download from the JRC Data Catalogue in an easy to-use spreadsheet format. This knowledge base is complemented by a Technical Report, which provides an in-depth meta-analysis of the approaches being used and a separately published Executive Summary intended for the general reader.

The collection shows that in vitro models based on a variety of immortalised cell lines are the most representative approach used for breast cancer research. Although monolayer cultures based on cancer-like cell lines are convenient to study aspects of breast cancer, their simplicity limits their relevance.

Attention has been shifting therefore to the development and application of three-dimensional tissue models since they can better capture the complexity and heterogeneity that characterise human breast tumours. Three-dimensional models include spheroids, known also as ‘mammospheres’, engineered tissues grown on biocompatible polymer scaffolds, and organoids which reflect more complex aspects of tissue composition and micro-architecture.

 

More information on the animal models of breast cancer :

https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.593337/full

http://www.bioline.org.br/pdf?zr20051

https://journals.biologists.com/dmm/article/10/4/359/20822/In-vivo-models-in-breast-cancer-research-progress

https://www.dovepress.com/application-of-animal-models-in-cancer-research-recent-progress-and-fu-peer-reviewed-fulltext-article-CMAR

 


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Last edited: 2 October 2023 10:07

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