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The Molecular Pathology of Chemoresistance During the Therapeutic Response in Breast Cancer

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Precision Molecular Pathology of Breast Cancer

Part of the book series: Molecular Pathology Library ((MPLB,volume 10))

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Abstract

Chemoresistance to conventional agents is a challenge for the successful treatment of breast cancer. The response, or absence of response, can be quantified through the use of conventional histopathology. However, there are currently no molecular markers that can improve on current routine pathology practice. Nevertheless, much is being revealed about the underlying biology of chemoresistance due to the rise in neoadjuvant therapy and the opportunities this affords researchers to examine tumour responses to therapy at the molecular level. Novel molecular markers of tumour response to therapy may become the mainstay of pathological practice in the coming years. Tumour resistance to chemotherapy may be innate or acquired after exposure to therapeutic insult and is the result of several molecular mechanisms responding to the presence of a cytotoxic compound. Systemically, resistance can be the consequence of detoxification in the liver where CYP clearance enzymes metabolize many chemotherapy agents. At the level of the tumour itself, drug efflux pumps are able to export many common frontline chemotherapeutics and so limit their cytotoxicity. However, many efflux pumps exist with broad and overlapping substrate ranges; redundancy in this system has hampered previous studies. There is a persuasive need for gene network analyses to gain understanding in this area. The complexity of the development of chemoresistance is further augmented by the existence of compartments of cells within many tumours that are able to reseed tumour growth after therapy has been completed. These cells, which may either be cancer stem cells or normal tumour cells induced to undergo the epithelial–mesenchymal transition, are characterized by chemoresistance and their ability to reseed tumour growth. Heterogeneous responses to chemotherapy are in part explained by the activation of multiple signalling pathways which, in a tumour, work to promote cell survival. Notch and AKT signalling for example are activated by multiple chemotherapeutics, induce expression of drug detoxification mechanisms, suppress apoptosis and enhance cancer stem-cell features. The heterogenic activation of such pathways both intra- and inter-tumourally emphasizes the need for network approaches to improve our understanding of these phenomena.

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Authors and Affiliations

  1. Department of Mathematical and Physical Sciences (MAPS), School of Food Science and Nutrition, Woodhouse Lane, University of Leeds, Leeds, West Yorkshire, LS2 9JT, UK

    James L. Thorne

  2. Leeds Institute of Cancer and Pathology (LICAP), St. James University Hospital/University of Leeds, Beckett Street, Leeds, West Yorkshire, LS9 7TF, UK

    Andrew M. Hanby

  3. Leeds Institute of Biologial and Clinical Sciences (LIBACS), St. James University Hospital/University of Leeds, Beckett Street, Leeds, West Yorkshire, LS9 7TF, UK

    Thomas A. Hughes

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  1. James L. Thorne
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  2. Andrew M. Hanby
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  3. Thomas A. Hughes
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Correspondence to Andrew M. Hanby .

Editor information

Editors and Affiliations

  1. Department of Pathology, University of Massachusetts Medical School, UMassMemorial Medical Center, Worcester, Massachusetts, USA

    Ashraf Khan

  2. Department of Histopathology, University of Nottingham, Nottingham, United Kingdom

    Ian O. Ellis

  3. Leeds Institute of Cancer and Pathology, St. James University Hospital, Leeds, West Yorkshire, United Kingdom

    Andrew M. Hanby

  4. Department of Pathology, University of Massachusetts Medical School, UMassMemorial Medical Center, Worcester, Massachusetts, USA

    Ediz F. Cosar

  5. Department of Histopathology, University of Nottingham, Nottingham, United Kingdom

    Emad A. Rakha

  6. Department of Pathology, University of Massachusetts Medical School, UMassMemorial Medical Center, Worcester, Massachusetts, USA

    Dina Kandil

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Thorne, J.L., Hanby, A.M., Hughes, T.A. (2015). The Molecular Pathology of Chemoresistance During the Therapeutic Response in Breast Cancer. In: Khan, A., Ellis, I., Hanby, A., Cosar, E., Rakha, E., Kandil, D. (eds) Precision Molecular Pathology of Breast Cancer. Molecular Pathology Library, vol 10. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2886-6_17

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