TY - JOUR
T1 - Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer
AU - Li, Yang
AU - Zou, Lihua
AU - Li, Qiyuan
AU - Haibe-Kains, Benjamin
AU - Tian, Ruiyang
AU - Le, Yan
AU - Desmedt, Christine
AU - Sotiriou, Christos
AU - Szallasi, Zoltan
AU - Iglehart, J. Dirk
AU - Richardson, Andrea L.
AU - Wang, Zhigang Charles
N1 - Funding Information:
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.
PY - 2010/2
Y1 - 2010/2
N2 - 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.
AB - 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.
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U2 - 10.1038/nm.2090
DO - 10.1038/nm.2090
M3 - Article
C2 - 20098429
AN - SCOPUS:76349095348
SN - 1078-8956
VL - 16
SP - 214
EP - 218
JO - Nature medicine
JF - Nature medicine
IS - 2
ER -