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

Yang Li, Lihua Zou, Qiyuan Li, Benjamin Haibe-Kains, Ruiyang Tian, Yan Le, Christine Desmedt, Christos Sotiriou, Zoltan Szallasi, J. Dirk Iglehart, Andrea L. Richardson, Zhigang Charles Wang

Research output: Contribution to journalArticlepeer-review

280 Scopus citations

Abstract

Adjuvant chemotherapy for breast cancer after surgery has effectively lowered metastatic recurrence rates. 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 outcomes. 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.

Original languageEnglish (US)
Pages (from-to)214-218
Number of pages5
JournalNature Medicine
Volume16
Issue number2
DOIs
StatePublished - Feb 2010

Funding

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.

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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