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PMID: 20098429 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature medicine ·Vol. 16 ·No. 2 ·2010-02-00 ·Pages 214-8

Li Y, Zou L, Li Q, Haibe-Kains B, Tian R, Li Y, Desmedt C, Sotiriou C, Szallasi Z, Iglehart JD, Richardson AL, Wang ZC

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.

MeSH Terms
Antineoplastic Combined Chemotherapy Protocols/therapeutic use Breast Neoplasms/drug therapy,genetics,pathology Cell Line, Tumor Chromosomes, Human, Pair 8 Cohort Studies Drug Resistance, Neoplasm Female Gene Amplification Humans Membrane Proteins/genetics Oncogene Proteins/genetics Recurrence
Chemicals
LAPTM4B protein, human Membrane Proteins Oncogene Proteins
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Li Yang
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Zou Lihua
Li Qiyuan
Haibe-Kains Benjamin
Tian Ruiyang
Li Yan
Desmedt Christine
Sotiriou Christos
Szallasi Zoltan
Iglehart J Dirk
Richardson Andrea L
Wang Zhigang Charles
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm.2090
Published
2010-02-00
Epub
2010-00-24
Pages
214-8
Language
English
Region
United States
NLM ID
9502015
PMCID
PMC2826790
Subset
IM
Grants
NCI NIH HHS · P50 CA089393-01 · United States
NCI NIH HHS · P50 CA089393 · United States
NCI NIH HHS · BC053041 · United States
NCI NIH HHS · P50 CA089393-10 · United States
NCI NIH HHS · CA89393 · United States
External Links
PubMed source DOI: 10.1038/nm.2090 PMC Full Text View journal details
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