Trastuzumab resistance induces EMT to transform HER2 + PTEN' to a triple negative breast cancer that requires unique treatment options

Joseph P. Burnett, Hasan Korkaya, Maria D. Ouzounova, Hui Jiang, Sarah J. Conley, Bryan W. Newman, Lichao Sun, Jamie N. Connarn, Ching Shih Chen, Ning Zhang, Max S. Wicha, Duxin Sun

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Although trastuzumab is an effective treatment in early stage HER2 + breast cancer the majority of advanced HER2 + breast cancers develop trastuzumab resistance, especially in the 40% of breast cancers with loss of PTEN. However, HER2 + breast cancer patients continue to receive trastuzumab regardless PTEN status and the consequence of therapy in these patients is unknown. We demonstrate that continued use of trastuzumab in HER2 + cells with loss of PTEN induces the epithelial-mesenchymal transition (EMT) and transform HER2 + to a triple negative breast cancer. These transformed cells exhibited mesenchymal morphology and gene expression markers, while parent HER2 + cells showed epithelial morphology and markers. The transformed cells exhibited loss of dependence on ERBB family signaling (such as HER2, HER3, HER4, BTC, HRG, EGF) and reduced estrogen and progesterone receptors. Continued use of trastuzumab in HER2 + PTEN' cells increased the frequency of cancer stem cells (CSCs) and metastasis potential. Strikingly, parental HER2 + cells and transformed resistant cells respond to treatment differently. Transformed resistant cells were sensitive to chemical probe (sulforaphane) through inhibition of IL-6/STAT3/NF-? B positive feedback loop whereas parental HER2 + cells did not respond. This data suggests that trastuzumab resistance in HER2 + PTEN' breast cancer induces EMT and subtype switching, which requires unique treatment options.

Original languageEnglish (US)
Article number15821
JournalScientific Reports
Volume5
DOIs
StatePublished - Nov 2 2015

Fingerprint

Triple Negative Breast Neoplasms
Epithelial-Mesenchymal Transition
Breast Neoplasms
Therapeutics
Neoplastic Stem Cells
Trastuzumab
Progesterone Receptors
Epidermal Growth Factor
Estrogen Receptors
Interleukin-6
Epithelial Cells
Neoplasm Metastasis
Gene Expression

ASJC Scopus subject areas

  • General

Cite this

Trastuzumab resistance induces EMT to transform HER2 + PTEN' to a triple negative breast cancer that requires unique treatment options. / Burnett, Joseph P.; Korkaya, Hasan; Ouzounova, Maria D.; Jiang, Hui; Conley, Sarah J.; Newman, Bryan W.; Sun, Lichao; Connarn, Jamie N.; Chen, Ching Shih; Zhang, Ning; Wicha, Max S.; Sun, Duxin.

In: Scientific Reports, Vol. 5, 15821, 02.11.2015.

Research output: Contribution to journalArticle

Burnett, JP, Korkaya, H, Ouzounova, MD, Jiang, H, Conley, SJ, Newman, BW, Sun, L, Connarn, JN, Chen, CS, Zhang, N, Wicha, MS & Sun, D 2015, 'Trastuzumab resistance induces EMT to transform HER2 + PTEN' to a triple negative breast cancer that requires unique treatment options', Scientific Reports, vol. 5, 15821. https://doi.org/10.1038/srep15821
Burnett, Joseph P. ; Korkaya, Hasan ; Ouzounova, Maria D. ; Jiang, Hui ; Conley, Sarah J. ; Newman, Bryan W. ; Sun, Lichao ; Connarn, Jamie N. ; Chen, Ching Shih ; Zhang, Ning ; Wicha, Max S. ; Sun, Duxin. / Trastuzumab resistance induces EMT to transform HER2 + PTEN' to a triple negative breast cancer that requires unique treatment options. In: Scientific Reports. 2015 ; Vol. 5.
@article{75fdf5bd45764ba3a58e9815a8b1c684,
title = "Trastuzumab resistance induces EMT to transform HER2 + PTEN' to a triple negative breast cancer that requires unique treatment options",
abstract = "Although trastuzumab is an effective treatment in early stage HER2 + breast cancer the majority of advanced HER2 + breast cancers develop trastuzumab resistance, especially in the 40{\%} of breast cancers with loss of PTEN. However, HER2 + breast cancer patients continue to receive trastuzumab regardless PTEN status and the consequence of therapy in these patients is unknown. We demonstrate that continued use of trastuzumab in HER2 + cells with loss of PTEN induces the epithelial-mesenchymal transition (EMT) and transform HER2 + to a triple negative breast cancer. These transformed cells exhibited mesenchymal morphology and gene expression markers, while parent HER2 + cells showed epithelial morphology and markers. The transformed cells exhibited loss of dependence on ERBB family signaling (such as HER2, HER3, HER4, BTC, HRG, EGF) and reduced estrogen and progesterone receptors. Continued use of trastuzumab in HER2 + PTEN' cells increased the frequency of cancer stem cells (CSCs) and metastasis potential. Strikingly, parental HER2 + cells and transformed resistant cells respond to treatment differently. Transformed resistant cells were sensitive to chemical probe (sulforaphane) through inhibition of IL-6/STAT3/NF-? B positive feedback loop whereas parental HER2 + cells did not respond. This data suggests that trastuzumab resistance in HER2 + PTEN' breast cancer induces EMT and subtype switching, which requires unique treatment options.",
author = "Burnett, {Joseph P.} and Hasan Korkaya and Ouzounova, {Maria D.} and Hui Jiang and Conley, {Sarah J.} and Newman, {Bryan W.} and Lichao Sun and Connarn, {Jamie N.} and Chen, {Ching Shih} and Ning Zhang and Wicha, {Max S.} and Duxin Sun",
year = "2015",
month = "11",
day = "2",
doi = "10.1038/srep15821",
language = "English (US)",
volume = "5",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Trastuzumab resistance induces EMT to transform HER2 + PTEN' to a triple negative breast cancer that requires unique treatment options

AU - Burnett, Joseph P.

AU - Korkaya, Hasan

AU - Ouzounova, Maria D.

AU - Jiang, Hui

AU - Conley, Sarah J.

AU - Newman, Bryan W.

AU - Sun, Lichao

AU - Connarn, Jamie N.

AU - Chen, Ching Shih

AU - Zhang, Ning

AU - Wicha, Max S.

AU - Sun, Duxin

PY - 2015/11/2

Y1 - 2015/11/2

N2 - Although trastuzumab is an effective treatment in early stage HER2 + breast cancer the majority of advanced HER2 + breast cancers develop trastuzumab resistance, especially in the 40% of breast cancers with loss of PTEN. However, HER2 + breast cancer patients continue to receive trastuzumab regardless PTEN status and the consequence of therapy in these patients is unknown. We demonstrate that continued use of trastuzumab in HER2 + cells with loss of PTEN induces the epithelial-mesenchymal transition (EMT) and transform HER2 + to a triple negative breast cancer. These transformed cells exhibited mesenchymal morphology and gene expression markers, while parent HER2 + cells showed epithelial morphology and markers. The transformed cells exhibited loss of dependence on ERBB family signaling (such as HER2, HER3, HER4, BTC, HRG, EGF) and reduced estrogen and progesterone receptors. Continued use of trastuzumab in HER2 + PTEN' cells increased the frequency of cancer stem cells (CSCs) and metastasis potential. Strikingly, parental HER2 + cells and transformed resistant cells respond to treatment differently. Transformed resistant cells were sensitive to chemical probe (sulforaphane) through inhibition of IL-6/STAT3/NF-? B positive feedback loop whereas parental HER2 + cells did not respond. This data suggests that trastuzumab resistance in HER2 + PTEN' breast cancer induces EMT and subtype switching, which requires unique treatment options.

AB - Although trastuzumab is an effective treatment in early stage HER2 + breast cancer the majority of advanced HER2 + breast cancers develop trastuzumab resistance, especially in the 40% of breast cancers with loss of PTEN. However, HER2 + breast cancer patients continue to receive trastuzumab regardless PTEN status and the consequence of therapy in these patients is unknown. We demonstrate that continued use of trastuzumab in HER2 + cells with loss of PTEN induces the epithelial-mesenchymal transition (EMT) and transform HER2 + to a triple negative breast cancer. These transformed cells exhibited mesenchymal morphology and gene expression markers, while parent HER2 + cells showed epithelial morphology and markers. The transformed cells exhibited loss of dependence on ERBB family signaling (such as HER2, HER3, HER4, BTC, HRG, EGF) and reduced estrogen and progesterone receptors. Continued use of trastuzumab in HER2 + PTEN' cells increased the frequency of cancer stem cells (CSCs) and metastasis potential. Strikingly, parental HER2 + cells and transformed resistant cells respond to treatment differently. Transformed resistant cells were sensitive to chemical probe (sulforaphane) through inhibition of IL-6/STAT3/NF-? B positive feedback loop whereas parental HER2 + cells did not respond. This data suggests that trastuzumab resistance in HER2 + PTEN' breast cancer induces EMT and subtype switching, which requires unique treatment options.

UR - http://www.scopus.com/inward/record.url?scp=84946198115&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84946198115&partnerID=8YFLogxK

U2 - 10.1038/srep15821

DO - 10.1038/srep15821

M3 - Article

C2 - 26522776

AN - SCOPUS:84946198115

VL - 5

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 15821

ER -