Spontaneous epithelial-mesenchymal transition and resistance to HER-2-targeted therapies in HER-2-positive luminal breast cancer.

Resistance to trastuzumab, a rationally designed HER-2-targeting antibody, remains a major hurdle in the management of HER-2-positive breast cancer. Preclinical studies suggest the mechanisms of trastuzumab resistance are numerous. Unfortunately, the majority of these studies are based around HER-2-...

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Autores principales: David Lesniak, Siham Sabri, Yaoxian Xu, Kathryn Graham, Pravin Bhatnagar, Mavanur Suresh, Bassam Abdulkarim
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Publicado: Public Library of Science (PLoS) 2013
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spelling oai:doaj.org-article:ea5bd0be082147b9a2a176976bfc2bc92021-11-18T08:58:15ZSpontaneous epithelial-mesenchymal transition and resistance to HER-2-targeted therapies in HER-2-positive luminal breast cancer.1932-620310.1371/journal.pone.0071987https://doaj.org/article/ea5bd0be082147b9a2a176976bfc2bc92013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23991019/?tool=EBIhttps://doaj.org/toc/1932-6203Resistance to trastuzumab, a rationally designed HER-2-targeting antibody, remains a major hurdle in the management of HER-2-positive breast cancer. Preclinical studies suggest the mechanisms of trastuzumab resistance are numerous. Unfortunately, the majority of these studies are based around HER-2-positive (HER-2+) luminal cell lines. The role of epithelial to mesenchymal transition (EMT), a genetic program that confers a basal phenotype, may represent a novel mechanism of escape for HER-2+ luminal cells from trastuzumab treatment. Here we investigated this possibility using a model of clonal selection in HER-2+ luminal breast cancer cells. Following a random isolation and expansion of "colony clusters" from SKBR-3 cell lines, several colony clusters underwent a spontaneous EMT in-vitro. In addition to expression of conventional EMT markers, all mesenchymal colony clusters displayed a predominant CD44+/CD24- phenotype with decreased HER-2 expression and elevated levels of a β1-integrin isoform with a high degree of N-glycosylation. Treatment with a β1-integrin function-blocking antibody, AIIB2, preferentially decreased the N-glycosylated form of β1-integrin, impaired mammosphere formation and restored epithelial phenotype in mesenchymal colony clusters. Using this model we provide the first clear evidence that resistance to trastuzumab (and lapatinib) can occur spontaneously as HER-2+ cells shift from a luminal to a basal/mesenchymal phenotype following EMT. While the major determinant of trastuzumab resistance in mesenchymal colony clusters is likely the down regulation of the HER-2 protein, our evidence suggests that multiple factors may contribute, including expression of N-glycosylated β1-integrin.David LesniakSiham SabriYaoxian XuKathryn GrahamPravin BhatnagarMavanur SureshBassam AbdulkarimPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 8, p e71987 (2013)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
David Lesniak
Siham Sabri
Yaoxian Xu
Kathryn Graham
Pravin Bhatnagar
Mavanur Suresh
Bassam Abdulkarim
Spontaneous epithelial-mesenchymal transition and resistance to HER-2-targeted therapies in HER-2-positive luminal breast cancer.
description Resistance to trastuzumab, a rationally designed HER-2-targeting antibody, remains a major hurdle in the management of HER-2-positive breast cancer. Preclinical studies suggest the mechanisms of trastuzumab resistance are numerous. Unfortunately, the majority of these studies are based around HER-2-positive (HER-2+) luminal cell lines. The role of epithelial to mesenchymal transition (EMT), a genetic program that confers a basal phenotype, may represent a novel mechanism of escape for HER-2+ luminal cells from trastuzumab treatment. Here we investigated this possibility using a model of clonal selection in HER-2+ luminal breast cancer cells. Following a random isolation and expansion of "colony clusters" from SKBR-3 cell lines, several colony clusters underwent a spontaneous EMT in-vitro. In addition to expression of conventional EMT markers, all mesenchymal colony clusters displayed a predominant CD44+/CD24- phenotype with decreased HER-2 expression and elevated levels of a β1-integrin isoform with a high degree of N-glycosylation. Treatment with a β1-integrin function-blocking antibody, AIIB2, preferentially decreased the N-glycosylated form of β1-integrin, impaired mammosphere formation and restored epithelial phenotype in mesenchymal colony clusters. Using this model we provide the first clear evidence that resistance to trastuzumab (and lapatinib) can occur spontaneously as HER-2+ cells shift from a luminal to a basal/mesenchymal phenotype following EMT. While the major determinant of trastuzumab resistance in mesenchymal colony clusters is likely the down regulation of the HER-2 protein, our evidence suggests that multiple factors may contribute, including expression of N-glycosylated β1-integrin.
format article
author David Lesniak
Siham Sabri
Yaoxian Xu
Kathryn Graham
Pravin Bhatnagar
Mavanur Suresh
Bassam Abdulkarim
author_facet David Lesniak
Siham Sabri
Yaoxian Xu
Kathryn Graham
Pravin Bhatnagar
Mavanur Suresh
Bassam Abdulkarim
author_sort David Lesniak
title Spontaneous epithelial-mesenchymal transition and resistance to HER-2-targeted therapies in HER-2-positive luminal breast cancer.
title_short Spontaneous epithelial-mesenchymal transition and resistance to HER-2-targeted therapies in HER-2-positive luminal breast cancer.
title_full Spontaneous epithelial-mesenchymal transition and resistance to HER-2-targeted therapies in HER-2-positive luminal breast cancer.
title_fullStr Spontaneous epithelial-mesenchymal transition and resistance to HER-2-targeted therapies in HER-2-positive luminal breast cancer.
title_full_unstemmed Spontaneous epithelial-mesenchymal transition and resistance to HER-2-targeted therapies in HER-2-positive luminal breast cancer.
title_sort spontaneous epithelial-mesenchymal transition and resistance to her-2-targeted therapies in her-2-positive luminal breast cancer.
publisher Public Library of Science (PLoS)
publishDate 2013
url https://doaj.org/article/ea5bd0be082147b9a2a176976bfc2bc9
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