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Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer

Nature Medicine volume 16, pages 214–218 (2010)Cite this article

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Abstract

Adjuvant chemotherapy for breast cancer after surgery has effectively lowered metastatic recurrence rates1. However, a considerable proportion of women suffer recurrent cancer at distant metastatic sites despite adjuvant treatment. Identification of the genes crucial for tumor response to specific chemotherapy drugs is a challenge but is necessary to improve outcomes2. By using integrated genomics, we identified a small number of overexpressed and amplified genes from chromosome 8q22 that were associated with early disease recurrence despite anthracycline-based adjuvant chemotherapy. We confirmed the association in an analysis of multiple independent cohorts. SiRNA-mediated knockdown of either of two of these genes, the antiapoptotic gene YWHAZ and a lysosomal gene LAPTM4B, sensitized tumor cells to anthracyclines, and overexpression of either of the genes induced anthracycline resistance. Overexpression of LAPTM4B resulted in sequestration of the anthracycline doxorubicin, delaying its appearance in the nucleus. Overexpression of these two genes was associated with poor tumor response to anthracycline treatment in a neoadjuvant chemotherapy trial in women with primary breast cancer. Our results suggest that 8q22 amplification and overexpression of LAPTM4B and YWHAZ contribute to de novo chemoresistance to anthracyclines and are permissive for metastatic recurrence. Overexpression of these two genes may predict anthracycline resistance and influence selection of chemotherapy.

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Figure 1: 8q22 amplification, gene expression and cancer recurrence.
Figure 2: Knockdown of 8q22 genes by siRNA in tumor cell lines to determine the effect on sensitivity to anthracycline chemotherapy.
Figure 3: LAPTM4B expression, intracellular doxorubicin distribution and drug-induced DNA damage in breast cancer cell lines.
Figure 4: LAPTM4B and YWHAZ expression and pCR to neoadjuvant chemotherapy.

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Acknowledgements

We thank C. Lee, A. Aggarwal, E. Fox, P. Hollasch, M. Berkeley, R. Gelman, W. Luo, X. Lu and members of the Richardson-Wang lab for their advice and assistance. We also thank J.E. Garber, A.C. Eklund, N. Juul and R.-L. Zhou for helpful discussions and advice, and D. Silver and J.-Y. Kim for their critical review of this manuscript. The pWZL expression vector and HMECs carrying a dominant-negative allele of the gene encoding p53 were generously provided by J. Zhao, (Dana-Farber Cancer Institute). This work was supported by the Breast Cancer Research Foundation in New York. Support also came from the US National Cancer Institute Specialized Program of Research Excellence in Breast Cancer at Harvard (CA89393) and a Department of Defense Concept Award (BC053041). The Trial of Principle trial was supported by the Fondation Luxembourgeoise contre le Cancer, by the Fonds National de la Recherche Scientifique (C.S., B.H.-K., C.D.), by the Brussels Region, by the Walloon Region (BIOWIN) and by the European Commission through the 'Advancing Clinico-Genomic Trials' project (FP6-2005-IST-026996). We thank Sanofi-Aventis for their support with adjuvant Taxotere, and we thank all of the participants in the Trial of Principle.

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Author notes

  1. Yang Li, Lihua Zou, Qiyuan Li, Andrea L Richardson and Zhigang Charles Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Yang Li, Lihua Zou, Ruiyang Tian, Yan Li, J Dirk Iglehart, Andrea L Richardson & Zhigang Charles Wang

  2. Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Yang Li, J Dirk Iglehart & Zhigang Charles Wang

  3. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA

    Lihua Zou

  4. Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark

    Qiyuan Li & Zoltan Szallasi

  5. Medical Oncology Department, Jules Bordet Institute, Brussels, Belgium

    Benjamin Haibe-Kains, Christine Desmedt & Christos Sotiriou

  6. Machine Learning Group, Université Libre de Bruxelles, Brussels, Belgium

    Benjamin Haibe-Kains

  7. Children's Hospital Informatics Program at the Harvard–Massachusetts Institute of Technology Division of Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts, USA

    Zoltan Szallasi

  8. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Andrea L Richardson

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Contributions

A.L.R. and Z.C.W. designed the experiments and supervised the project. Yang Li performed the in vitro laboratory experiments including generating complementary DNA vector constructs, gene transfer and knockdown, RT-PCR and western blot analysis, and drug sensitivity and localization studies. L.Z. performed the PAM data analysis and statistics. Q.L., under supervision of Z.S., performed bioinformatic analysis on validation data sets and the cisplatin trial data set. R.T. performed apoptosis assays. Yan Li contributed to the preparation of cDNA vector constructs. C.D., C.S. and B.H.-K. performed the epirubicin trial and provided clinical data and analysis. A.L.R. provided the DF/HCC and cisplatin trial clinical samples and performed gene expression array analysis. Z.C.W. performed the SNP array analysis and scored the FISH assays. A.L.R., J.D.I. and Z.C.W. wrote the manuscript with comments from Yang Li, C.D., C.S. and Z.S.

Corresponding authors

Correspondence to Andrea L Richardson or Zhigang Charles Wang.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4, Supplementary Tables 2–3 and Supplementary Methods (PDF 987 kb)

Supplementary Table 1

PAM probe list (XLS 38 kb)

Supplementary Table 4

Sample features (XLS 57 kb)

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Li, Y., Zou, L., Li, Q. et al. Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer. Nat Med 16, 214–218 (2010). https://doi.org/10.1038/nm.2090

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