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Modelling breast cancer: one size does not fit all

Key Points

  • The models commonly used to investigate breast cancer, including breast cancer cell lines, xenografts and genetically engineered mice (GEM), are discussed. Their strengths and limitations, and how they can be optimally used and improved, are described.

  • Breast cancer cell lines share many of the genetic and genomic features of human breast cancers, including representing several breast cancer subtypes. Several cell lines may also serve as models to investigate tumour-initiating cell properties.

  • Utilization of cell lines as subtype systems in three-dimensional and heterotypic cultures represent powerful approaches to investigate the signalling interactions that contribute to breast cancer biology.

  • Xenografts of cell lines and breast cancer clinical isolates allow for the examination of human breast cancer cells in the context of the in vivo environment, as the cell culture environment cannot completely recapitulate the complex multicellular and cell–extracellular matrix interactions that are involved in the initiation and progression of breast cancer.

  • Genetically engineered mouse models of breast cancer exhibit many features of human breast cancer and thus provide invaluable models for investigating the biology and pathogenesis of this disease. The accumulating number of molecular profiling studies provide a framework for comparing GEM and human breast cancer.

  • Because of the complexity and heterogeneity of breast cancer no individual model recapitulates all aspects of this disease. Thus, an integrated and multi-systems approach is currently the strongest way to model this disease.

Abstract

Breast cancer is not a single disease, but is instead a collection of diseases that have distinct histopathological features, genetic and genomic variability, and diverse prognostic outcomes. Thus, no individual model would be expected to completely recapitulate this complex disease. Here, the models commonly used to investigate breast cancer including cell lines, xenografts and genetically engineered mice, are discussed to help address the question: what is the most powerful way to investigate this heterogeneous disease?

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Figure 1: The biology of breast cancer.
Figure 2: The identification of breast cancer subtypes by molecular profiling.
Figure 3: Culture methods and xenografts.
Figure 4: Molecular profiling of mammary tumours from GEM and comparison with human breast cancer profiles.

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Acknowledgements

We are grateful to C. Perou, C. Kuperwasser, M. Bissell, M. Wicha, J. Chang and M. Lewis for kindly providing preprints and sharing their data before publication. We would like to thank C. Allred for contributing the histopathology images and K. Schwertfeger for critical reading of the manuscript. We apologize to authors whose work was omitted owing to space limitations. Supported in part by 1K99CA127,361-01 awarded to T.V.-G. and CA16,303 awarded to J.M.R.

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Glossary

Triple negative subtype

A subtype of invasive ductal carcinoma that is ER, PR and ERBB2 negative.

Pleural effusion

A fluid, which contains tumour cells, that accumulates between the thin layers of tissue lining the lung and chest wall.

Limiting dilution transplantation

An experimental method for estimating the number of cells that have stem or progenitor or tumour-initiating behaviour within a population of cells.

Aldefluor

An aldehyde dehydrogenase (ALDH) substrate that allows the identification and isolation of stem or progenitor cells based on the observation that these cells have high ALDH activity.

Matrix compliance

The flexibility of the matrix surrounding the cells, which exerts forces that affect cell behaviour.

Homotypic

An interaction between cells of the same type.

Angiogenic switch

A shift in the net balance between positive and negative angiogenesis factors in which there are increased positive factors to promote the growth of new blood vessels in tumours.

Intravital microscopy

Fluorescence microscopy that allows the visualization of individual cells within living tissues or animals.

Fibrosis

The formation of excess fibrous connective tissue that results from a reactive process within the tumour stroma.

Dormant tumour-initiating cells

The cells within a tumour that are not actively cycling and are capable of giving rise to a new tumour.

Neoadjuvant chemotherapy

A drug treatment given to reduce the size of tumours before surgery.

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Vargo-Gogola, T., Rosen, J. Modelling breast cancer: one size does not fit all. Nat Rev Cancer 7, 659–672 (2007). https://doi.org/10.1038/nrc2193

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