Mouse Models of Breast Cancer: Platforms for Discovering Precision Imaging Diagnostics and Future Cancer Medicine

Manning, H. Charles; Buck, Jason R.; Cook, Rebecca S.

doi:10.2967/jnumed.115.157917

Cited by 38 publications

(47 citation statements)

References 46 publications

(48 reference statements)

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“…Metabolomic analysis of organic extracts provided further evidence for lipidic reprogramming in TNBC development and progression; in particular, 4T1 primary tumors displayed higher concentrations of cholesterol and phospholipids. These alterations reflect the avidity of proliferative cancer cells for lipids and cholesterol, a characteristic now considered a hallmark of cancer aggressiveness . MDA‐MB‐231‐Luc primary tumors also displayed high levels of TAGs, whose hydrolysis in adipocytes adjacent to cancer cells generates free fatty acids for use as an energy source by tumor cells for tumor progression .…”

Section: Discussionmentioning

confidence: 99%

“…These alterations reflect the avidity of proliferative cancer cells for lipids and cholesterol, 34 a characteristic now considered a hallmark of cancer aggressiveness. 34,35 MDA-MB-231-Luc primary tumors also displayed high levels of TAGs, whose hydrolysis in adipocytes adjacent to cancer cells generates free fatty acids for use as an energy source by tumor cells for tumor progression. 34 We observed spontaneous lung and ALN metastasis in both models; however, while studies suggest that the 4T1 model develops lung metastasis via the hematogenous route, 13 we discovered earlier evidence of distal metastasis and subsequent rapid development predominantly through the lymphatic system, as observed in two recent studies.…”

Section: Modeling Capacities Of the 4t1 And Mda-mb-231-luc Tnbc Modelsmentioning

confidence: 99%

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Characterization of triple‐negative breast cancer preclinical models provides functional evidence of metastatic progression

Arroyo‐Crespo

Armiñán

Charbonnier

et al. 2019

Intl Journal of Cancer

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Triple‐negative breast cancer (TNBC), an aggressive, metastatic and recurrent breast cancer (BC) subtype, currently suffers from a lack of adequately described spontaneously metastatic preclinical models that faithfully reproduce the clinical scenario. We describe two preclinical spontaneously metastatic TNBC orthotopic murine models for the development of advanced therapeutics: an immunodeficient human MDA‐MB‐231‐Luc model and an immunocompetent mouse 4T1 model. Furthermore, we provide a broad range of multifactorial analysis for both models that could provide relevant information for the development of new therapies and diagnostic tools. Our comparisons uncovered differential growth rates, stromal arrangements and metabolic profiles in primary tumors, and the presence of cancer‐associated adipocyte infiltration in the MDA‐MB‐231‐Luc model. Histopathological studies highlighted the more rapid metastatic spread to the lungs in the 4T1 model following a lymphatic route, while we observed both homogeneous (MDA‐MB‐231‐Luc) and heterogeneous (4T1) metastatic spread to axillary lymph nodes. We encountered unique metabolomic signatures in each model, including crucial amino acids and cell membrane components. Hematological analysis demonstrated severe leukemoid and lymphoid reactions in the 4T1 model with the partial reestablishment of immune responses in the immunocompromised MDA‐MB‐231‐Luc model. Additionally, we discovered β‐immunoglobulinemia and increased basal levels of G‐CSF correlating with a metastatic switch, with G‐CSF also promoting extramedullary hematopoiesis (both models) and causing hepatosplenomegaly (4T1 model). Overall, we believe that the characterization of these preclinical models will foster the development of advanced therapeutic strategies for TNBC treatment, especially for the treatment of patients presenting both, primary tumors and metastatic spread.

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Section: Discussionmentioning

confidence: 99%

Section: Modeling Capacities Of the 4t1 And Mda-mb-231-luc Tnbc Modelsmentioning

confidence: 99%

Characterization of triple‐negative breast cancer preclinical models provides functional evidence of metastatic progression

Arroyo‐Crespo

Armiñán

Charbonnier

et al. 2019

Intl Journal of Cancer

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“…Currently several mice models, such as genetically engineered mouse models and patientderived tumor xenograft, with some strengths, have been introduced, but their development is time-consuming and expensive. [3][4][5] The 4T1 is an immunocompetent syngeneic mouse tumor that is known as TNBC model. 3,6,7 The tumor growth and metastatic spread of 4T1 tumors also resemble human breast cancer.…”

Section: Introductionmentioning

confidence: 99%

“…[3][4][5] The 4T1 is an immunocompetent syngeneic mouse tumor that is known as TNBC model. 3,6,7 The tumor growth and metastatic spread of 4T1 tumors also resemble human breast cancer. 6 The role of angiogenesis in TNBC is more outstanding than other breast cancer types, because the lymphatic vessel density, microvessel density (MVD) and vascular invasion which are related to vascular endothelial growth factor (VEGF) family are momentous in TNBC.…”

Section: Introductionmentioning

confidence: 99%

Expression of Diverse Angiogenesis Factor in Different Stages of the 4T1 Tumor as a Mouse Model of Triple-Negative Breast Cancer

et al. 2020

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Purpose: Triple-negative breast cancer (TNBC) is specified by high vascularity and repetitious metastasis. Although several studies have indicated that angiogenesis has an important role in invasive breast cancer, a suitable model of TNBC that can show the exact onset of angiogenesis factors still needs to be developed. The purpose of this study is to determine the expression level of angiogenesis factors in different clinical stages of the 4T1 tumor as TNBC mouse model. Methods: Twenty mice were injected by the 4T1 cell line, and four mice selected as healthy controls. Following by tumor induction, the mice were randomly put into four groups, each contains four mice. Once the tumor volume reached to the early stage (<100 mm3 ), intermediate stage (100-300 mm3 ), advanced stage (300-500 mm3 ), and end stage (>500 mm3 ), they were removed by surgery. Then, the expression levels of Hif1α, VEGFR1, and VEGFR2 genes, as well as tumor markers of VEGF, bFGF and CD31, were evaluated by qPCR and immunohistochemistry (IHC) respectively. The statistical analysis was done by SPSS version 16. Results: TNBC tumors were confirmed and multi-foci metastasis in the lung were seen. The mRNA and protein expression levels of the angiogenesis factors increased in the early stage and as the tumor grew, their expression level enhanced dramatically. Conclusion: The 4T1 syngeneic mouse tumor may serve as an appropriate TNBC model for further investigation of the angiogenesis and therapies. Moreover, angiogenesis factors are induced before the advanced stage, and anti-angiogenesis therapy is necessary to be considered at the first line of treatment in TBNC.

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“…Advances in molecular biology techniques have generated relevant mouse models (i.e., patientderived tumor models and genetically engineered models). These mouse models enable biomarker discovery for early detection of cancer [17], to identify non-responders to a particular treatment [18], and to classify tumors as being drug-sensitive or drug-resistant [19]. Excitingly, computational analyses are being combined with pre-clinical models to identify biomarkers for early detection and progression [17,19].…”

Section: Introductionmentioning

confidence: 99%

Mechanistic modeling quantifies the influence of tumor growth kinetics on the response to anti-angiogenic treatment

Gaddy

Finley

2017

Preprint

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Tumors exploit angiogenesis, the formation of new blood vessels from pre-existing vasculature, in order to obtain nutrients required for continued growth and proliferation. Targeting factors that regulate angiogenesis, including the potent promoter vascular endothelial growth factor (VEGF), is therefore an attractive strategy for inhibiting tumor growth. Computational modeling can be used to identify tumor-specific properties that influence the response to anti-angiogenic strategies. Here, we build on our previous systems biology model of VEGF transport and kinetics in tumor-bearing mice to include a tumor compartment whose volume depends on the "angiogenic signal" produced when VEGF binds to its receptors on tumor endothelial cells. We trained and validated the model using published in vivo measurements of xenograft tumor volume, producing a model that accurately predicts the tumor's response to anti-angiogenic treatment. We applied the model to investigate how tumor growth kinetics influence the response to anti-angiogenic treatment targeting VEGF. Based on multivariate regression analysis, we found that certain intrinsic kinetic parameters that characterize the growth of tumors could successfully predict response to anti-VEGF treatment, the reduction in tumor volume. Lastly, we use the trained model to predict the response to anti-VEGF therapy for tumors expressing different levels of VEGF receptors. The model predicts that certain tumors are more sensitive to treatment than others, and the response to treatment shows a nonlinear dependence on the VEGF receptor expression. Overall, this model is a useful tool for predicting how tumors will respond to anti-VEGF treatment, and it complements pre-clinical in vivo mouse studies.

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Mouse Models of Breast Cancer: Platforms for Discovering Precision Imaging Diagnostics and Future Cancer Medicine

Cited by 38 publications

References 46 publications

Characterization of triple‐negative breast cancer preclinical models provides functional evidence of metastatic progression

Characterization of triple‐negative breast cancer preclinical models provides functional evidence of metastatic progression

Expression of Diverse Angiogenesis Factor in Different Stages of the 4T1 Tumor as a Mouse Model of Triple-Negative Breast Cancer

Mechanistic modeling quantifies the influence of tumor growth kinetics on the response to anti-angiogenic treatment

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