Trastuzumab effects depend on HER2 phosphorylation in HER2-negative breast cancer cell lines.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Biomarkers, Tumor/*metabolism ; Breast Neoplasms/*drug therapy ; Protein Kinase Inhibitors/*pharmacology ; Receptor, ErbB-2/*metabolism ; Trastuzumab/*pharmacology; Biomarkers, Tumor/antagonists & inhibitors ; Breast/pathology ; Breast Neoplasms/pathology ; Canada ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cohort Studies ; Drug Resistance, Neoplasm ; Female ; Humans ; Phosphorylation ; Protein Kinase Inhibitors/therapeutic use ; Receptor, ErbB-2/antagonists & inhibitors ; Tissue Array Analysis ; Trastuzumab/therapeutic use ; Tyrosine/metabolism

The breast cancer (BC) biomarker HER2 (Human Epidermal Receptor 2) is overexpressed in 25% of BC. Only patients with HER2-positive tumors receive HER2-targeting therapies, like trastuzumab (Herceptin). However, some women with a HER2-negative BC could benefit from trastuzumab. This could be explained by the activation/phosphorylation of HER2 that can be recognized by trastuzumab. The aim of this study is to examine trastuzumab effects on HER2 phosphorylation at tyrosine Y877 (pHER2Y877). HER2 and pHER2Y877 status were evaluated in a cohort of BC patients representative of molecular subtypes distribution (n = 497) and in a series of BC cell lines (n = 7). Immunohistochemistry against pHER2Y877 was performed on tissue micro arrays. Cellular proliferation assays were performed on BC cell lines presenting different combinations of HER2 and pHER2Y877 status and treated with increasing doses of trastuzumab (0-150 μg/ml). The prevalence of pHER2Y877 in this cohort was 6%. Nearly 5% of patients with HER2-negative tumors (n = 406, 82%) overexpressed pHER2Y877. Among triple negative BC patients (n = 39, 8%), 7.7% expressed pHER2Y877. Trastuzumab treatment decreased cell proliferation in HER2-/pHER2Y877+ BC cell lines, to an extent comparable to what occurs in HER2+ cell lines, but did not affect HER2-/pHER2Y877- cell lines. Trastuzumab sensitivity in HER2-/pHER2Y877+ cell line is specific to HER2 tyrosine 877 phosphorylation. Hence, with further confirmation in a bigger cohort, trastuzumab treatment could be envisaged as a treatment option to women presenting with HER2-/pHER2+ tumors, representing more than 1000 BC women in Canada in 2019.
Competing Interests: The authors have declared that no competing interests exist.

Erratum in: PLoS One. 2020 Oct 15;15(10):e0241089. (PMID: 33057455)

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Canada CIHR

0 (Biomarkers, Tumor)
0 (Protein Kinase Inhibitors)
42HK56048U (Tyrosine)
EC 2.7.10.1 (ERBB2 protein, human)
EC 2.7.10.1 (Receptor, ErbB-2)
P188ANX8CK (Trastuzumab)

Date Created: 20200626 Date Completed: 20200909 Latest Revision: 20231103

20240105

PMC7316326

10.1371/journal.pone.0234991

32584853