Cited by 1,858HER2/EGFR in Cancer ResearchPI3K/AKT/mTOR signaling in cancerBreast Cancer Treatment Studies

PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients

Open access
Nagata, Yoichi, Lan, Keng-Hsueh, Zhou, Xiaoyan, Tan, Ming, Esteva, Francisco J., Sahin, Aysegul A., Klos, Kristine S., Li, Ping +5 more·2004·Cancer Cell

Abstract

The ErbB2-targeting antibody, trastuzumab (Herceptin), has remarkable therapeutic efficacy in certain patients with ErbB2-overexpressing tumors. The overall trastuzumab response rate, however, is limited and what determines trastuzumab response is poorly understood. Here we report that PTEN activation contributes to trastuzumab's antitumor activity. Trastuzumab treatment quickly increased PTEN membrane localization and phosphatase activity by reducing PTEN tyrosine phosphorylation via Src inhibition. Reducing PTEN in breast cancer cells by antisense oligonucleotides conferred trastuzumab resistance in vitro and in vivo. Patients with PTEN-deficient breast cancers had significantly poorer responses to trastuzumab-based therapy than those with normal PTEN. Thus, PTEN deficiency is a powerful predictor for trastuzumab resistance. Additionally, PI3K inhibitors rescued PTEN loss-induced trastuzumab resistance, suggesting that PI3K-targeting therapies could overcome this resistance.

Integrity signals

Registry

Crossref · 10.1016/j.ccr.2004.06.022

Cites

65 of 65 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

5 of the 70 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Authors
Nagata, Y., Lan, K.-H., Zhou, X., Tan, M., Esteva, F. J., Sahin, A. A., Klos, K. S., Li, P., Monia, B. P., Nguyen, N. T., Hortobagyi, G. N., Hung, M.-C., & Yu, D.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • Ionis Pharmaceuticals (United States) (US)
Corresponding author
Yu, Dihua
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2004-08
Volume
6
Issue
2
Pages
117-127
ISSN
1535-6108 (ISSN-L)
OpenAlex
W2059411043
Cited by
1,858
References
70
Citations by year
2026: 19 · 2025: 29 · 2024: 35 · 2023: 82 · 2022: 52 · 2021: 50 · 2020: 60 · 2019: 56 · 2018: 66 · 2017: 68 · 2016: 88 · 2015: 109 · 2014: 119 · 2013: 125 · 2012: 123
FWCI
43.34
Type
journal article
Language
en
Open access
Locations
  • Cancer Cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01ca060488-09)
  • National Cancer Institute (P01CA099031, 2R01-CA60488, P30CA016672)
Topics
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
Keywords
PTEN, trastuzumab, trastuzumab resistance, ERBB2, HER2-positive breast cancer, Src kinase inhibition, PI3K inhibitors, predictive biomarkers, antisense oligonucleotides
MeSH terms
Trastuzumab, Phosphoinositide-3 Kinase Inhibitors, Animals, Antibodies, Monoclonal, Antineoplastic Agents, Breast Neoplasms, Enzyme Activation, Enzyme Inhibitors, Female, Humans, Mice, Nude, Neoplasm Transplantation, Phosphoric Monoester Hydrolases, Proto-Oncogene Proteins, Genes, Tumor Suppressor, Oligonucleotides, Antisense, Protein Serine-Threonine Kinases, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, src-Family Kinases, Phosphatidylinositol 3-Kinases, Tumor Suppressor Proteins, Cell Line, Tumor, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice, Antibodies, Monoclonal, Humanized

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review