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Origins of breast cancer subtypes and therapeutic implications

Abstract

This Review summarizes and evaluates the current evidence for the cellular origins of breast cancer subtypes identified by different approaches such as histology, molecular pathology, genetic and gene-expression analysis. Emerging knowledge of the normal breast cell types has led to the hypothesis that the subtypes of breast cancer might arise from mutations or genetic rearrangements occurring in different populations of stem cells and progenitor cells. We describe the common distinguishing features of these breast cancer subtypes and explain how these features relate both to prognosis and to selection of the most appropriate therapy. Recent data indicate that breast tumors may originate from cancer stem cells. Consequently, inhibition of stem-cell self-renewal pathways should be explored because of the likelihood that residual stem cells might be resistant to current therapies.

Key Points

  • There are several approaches to classification of breast cancer, including histology, molecular pathology, genetic, and gene-expression analysis

  • Subtyping of breast cancer can enable prediction of response to treatment and prognosis

  • The subtypes of breast cancer might arise from different populations of stem cells and progenitor cells present in the normal mammary gland

  • Cancer stem cells might give rise to tumors, which could explain why some cancer cells are resistant to current therapies

  • Stem-cell self-renewal pathways may represent targets for new treatments

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Figure 1: Comparison of the histopathology, molecular pathology, genetic, and gene-expression analysis methods used to delineate breast cancer tumor subtypes and suggested current and future therapies in a historical context
Figure 2: The hypothesis of early divergence between the main subtypes of breast cancer is supported by histopathology, molecular pathology, genetic, and gene-expression analysis
Figure 3: A model of stem-cell hierarchy and how it may account for the origins of different subtypes of breast cancer via cancer stem cells

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Acknowledgements

We are very grateful for funding from Breakthrough Breast Cancer, Breast Cancer Campaign, Cancer Research UK, and Christie's Appeal.

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Correspondence to Robert B Clarke.

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Sims, A., Howell, A., Howell, S. et al. Origins of breast cancer subtypes and therapeutic implications. Nat Rev Clin Oncol 4, 516–525 (2007). https://doi.org/10.1038/ncponc0908

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