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SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B are markers of resistance to neoadjuvant chemotherapy in HER2-negative breast cancer

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Abstract

Response rates to chemotherapy remain highly variable in breast cancer patients. We set out to identify genes associated with chemotherapy resistance. We analyzed what is currently the largest single-institute set of gene expression profiles derived from breast cancers prior to a single neoadjuvant chemotherapy regimen (dose-dense doxorubicin and cyclophosphamide). We collected, gene expression-profiled, and analyzed 178 HER2-negative breast tumor biopsies (“NKI dataset”). We employed a recently developed approach for detecting imbalanced differential signal (DIDS) to identify markers of resistance to treatment. In contrast to traditional methods, DIDS is able to identify markers that show aberrant expression in only a small subgroup of the non-responder samples. We found a number of markers of resistance to anthracycline-based chemotherapy. We validated our findings in three external datasets, totaling 456 HER2-negative samples. Since these external sets included patients who received differing treatment regimens, the validated markers represent markers of general chemotherapy resistance. There was a highly significant overlap in the markers identified in the NKI dataset and the other three datasets. Five resistance markers, SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B, were identified in three of the four datasets (p value overlap < 1 × 10−6). These five genes identified resistant tumors that could not have been identified by merely taking ER status or proliferation into account. The identification of these genes might lead to a better understanding of the mechanisms involved in (clinically) observed chemotherapy resistance and could possibly assist in the recognition of breast cancers in which chemotherapy does not contribute to response or survival.

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Acknowledgments

This study was performed within the framework of CTMM, the Center for Translational Molecular Medicine (www.ctmm.nl), project Breast CARE (Grant 03O-104). We thank Bernard Asselain, Frederique Spyratos, and Patricia de-Cremoux for sharing the Curie data with us.

Conflict of interest

We declare that we have no conflicts of interest.

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Authors and Affiliations

  1. Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Jorma J. de Ronde & Lodewyk F. A. Wessels

  2. Department of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Jorma J. de Ronde, Esther H. Lips & Lennart Mulder

  3. Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Esther H. Lips, Lennart Mulder & Jelle Wesseling

  4. Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Andrew D. Vincent

  5. Central Microarray Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Marja Nieuwland & Ron Kerkhoven

  6. Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Marie-Jeanne T. F. D. Vrancken Peeters

  7. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Gabe S. Sonke & Sjoerd Rodenhuis

  8. Faculty of EEMCS, Delft University of Technology, Delft, The Netherlands

    Lodewyk F. A. Wessels

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  1. Jorma J. de Ronde
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Correspondence to Lodewyk F. A. Wessels.

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de Ronde, J.J., Lips, E.H., Mulder, L. et al. SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B are markers of resistance to neoadjuvant chemotherapy in HER2-negative breast cancer. Breast Cancer Res Treat 137, 213–223 (2013). https://doi.org/10.1007/s10549-012-2340-x

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  • DOI: https://doi.org/10.1007/s10549-012-2340-x

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